ASCO 12 Annual Meeting, June 1-5, 2012, Chicago, Illinois, USA
CRPC (Vaccines, Abiraterone, Cabazitaxel, Sipuleucel-T, MDV3100, ADT, other treatments,)
Vaccines
Phase I trial of NY-ESO-1/LAGE1 peptide vaccine for metastatic castration resistant prostate cancer
(mCRPC).
Abstract No:4643
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4643)
Author(s): Teresa Gray Hayes, Guru Sonpavde, Mingjun Wang, Yicheng Wang, Teresa Joe, Martha P.
Mims, Michael M. Ittmann, Thomas M. Wheeler, Adrian P. Gee, Rongfu F Wang; Michael E. DeBakey VA
Medical Center and Baylor College of Medicine, Houston, TX; Texas Oncology, Michael E. DeBakey VA
Medical Center, and Baylor College of Medicine, Houston, TX; The Methodist Hospital, Houston, TX; Baylor
College of Medicine, Houston, TX; Department of Pathology, Baylor College of Medicine, Houston, TX
Abstract:
Background: The NY-ESO-1 and LAGE-1 antigens are amplified in malignancies including prostate cancer.
Preclinical induction of immune responses and anti-tumor activity has been demonstrated upon
administration of these peptides. A phase I/II clinical trial evaluated the feasibility of a combined HLA class-I
and class-II peptide vaccine in mCRPC. Methods: Men with progressive mCRPC, Performance Status ≤2,
PSA ≥10 ng/ml and had appropriate HLA class I (A2) and class II haplotypes (DR4, DP4, DR13) were
eligible. Three groups with 3 patients each received the vaccine subcutaneously every 2 weeks for 6 doses.
Group 1 was treated with a peptide directed at a HLA class I haplotype (HLA A2), Group 2 was treated with a
peptide reacting to a HLA class II haplotype (DR4, DP4, or DR13), and Group 3 received peptides directed
at both Class I and II haplotypes. Group I and Group II received 1 dose of 1000 mcg and Group III received
doses of 1000 mcg for each of 2 peptides. Androgen-deprivation was continued. Results: Of 14 patients
enrolled, all were evaluable for toxicities and 9 patients completed all 6 treatments per amended protocol
and were evaluable for efficacy. The median baseline PSA was 85.19 ng/ml. Four patients were chemo
naive and 5 were post-docetaxel. One patient had a grade 5 event (myocardial infarction) unlikely therapyrelated. Potential therapy related toxicities were local grade 1 injection site erythema (n=5), fatigue (n=2), flulike symptoms (n=1), myalgias (n=1), anorexia (n=1), nausea (n=1) and leukocytosis (n=1). The median PSA
doubling time pre-therapy and during therapy were 3.1 and 4.92 months, respectively. The PSA-DT was
prolonged compared to baseline in 6 patients, including a negative PSA slope in 2 patients. Antigen-specific
immune response determined by ELISPOT was observed, and its association with slowing of PSA-doubling
time will be further examined. Conclusions: In men with mCRPC, HLA class-I and/or class-II restricted NYESO-1 and LAGE-1 peptides administered subcutaneously demonstrated excellent tolerability, slowing of
PSA doubling time and antigen-specific immune responses. Further development of peptide vaccines alone
or in combination with other regimens may be warranted.
Interim analysis of a phase II randomized clinical trial of samrium-153 (Sm-153) with or without PSATRICOM vaccine in metastatic castration-resistant prostate cancer after docetaxel.
Abstract No:2526
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 2526)
Author(s): Christopher Ryan Heery, Ravi A. Madan, Marijo Bilusic, Joseph W. Kim, Nishith K. Singh, Myrna
Rauckhorst, Clara Chen, William L. Dahut, Walter Michael Stadler, Robert S. DiPaola, Mark N. Stein, James
W. Hodge, Jeffrey Schlom, James L. Gulley; Medical Oncology Branch, National Cancer Institute, National
Institutes of Health, Bethesda, MD; Laboratory of Tumor Immunology and Biology and Medical Oncology
Branch, National Cancer Institute, Bethesda, MD; Medical Oncology Branch, National Cancer Institute,
Bethesda, MD; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
Department of Nuclear Medicine, Clinical Center, National Institutes of Health, Bethesda, MD; The University
of Chicago, Chicago, IL; Cancer Institute of New Jersey, New Brunswick, NJ; Laboratory of Tumor
Immunology and Biology, National Cancer Institute, Bethesda, MD; Laboratory of Tumor Immunology and
Biology, Center for Cancer Research, Bethesda, MD
Abstract:
Background: A prior randomized, placebo-controlled, multi-center phase 2 trial of PSA-TRICOM
(PROSTVAC) demonstrated an overall survival benefit. Sm-153 is a radiopharmaceutical that targets
osteoblastic bone lesions. Preclinical data indicated that Sm-153 could alter tumor phenotype, causing
upregulation of Fas, MHC Class I, and tumor-associated antigens, making tumor cells more amenable to
immune-mediated killing. Methods: This is a phase 2 multi-center trial design intended to randomize 68
patients (pts) to Sm-153 with or without PROSTVAC. Eligibility included castrate resistant prostate cancer
bone metastases, no visceral disease, prior docetaxel, ECOG ≤2, and normal organ function. Sm-153 was
given at 1mCi/kg IV on day 8 and then every 12 weeks. PROSTVAC was given on days 1, 15, 29, then every
4 weeks. The 1° endpoint is a comparison of progression-free survival at 4 months (mo) utilizing PCCWG,
but not PSA criteria. 68 patients will provide 80% power to detect a difference of 15% vs. 40% without
progression at 4 mo with a one-tailed alpha = 0.10 assuming Fisher’s exact test comparing these fractions as
the primary method of analysis. 2° endpoints are OS, ORR, PSA changes, immunologic, toxicity, and
palliation. Reported here is the result of a pre-specified interim analysis, which required ≥20% conditional
power to detect 15% vs. 40% without progression at 4 months for the trial to continue. Results: Of 37
enrolled pts, 3 were not evaluable for PFS. PFS and PSA findings are found below. Hematologic toxicities
(anemia, thrombocytopenia, neutropenia, or lymphocytopenia) are most common, with grade 3 or 4
thrombocytopenia occurring in 22% and 26% of treatment cycles on Arms A and B, respectively. The
conditional power for the comparison of fractions without progression at 4 mo is 77%. Conclusions: This
interim analysis suggests the combination of PROSTVAC and Sm-153 is well tolerated with similar toxicity
profile to Sm-153 alone. The early indication of improved TTP warrants continued study accrual.
Sm-153 Sm-153 + PROSTVAC
(A)
(B)
PFS
At 4 mo
2/17 (11.8%) 5/17 (29.4%)
Median PFS days
60
117
Pt # confirmed PSA decline
≥ 30%
0
4
≥ 50%
0
2
Prospect: A randomized, double-blind, phase III efficacy trial of PROSTVAC.
Abstract No:TPS4699
Citation:
J Clin Oncol 30, 2012 (suppl; abstr TPS4699)
Author(s): Olga Bandman; BN ImmunoTherapeutics, Mountain View, CA
Abstract:
Background: PROSTVAC is a candidate cancer vaccine comprised of two recombinant poxviral vectors:
vaccinia (V) and fowlpox (F), each with insertions of four human genes: PSA and three costimulatory
molecules (TRICOM) - LFA-3, B7.1 and ICAM-1. This off the shelf vaccine demonstrated a statistically
significant overall survival (OS) benefit of 8.5 months while displaying a favorable side effect profile in
patients (pts) with asymptomatic to minimally symptomatic prostate cancer (mCRPC) in a randomized,
placebo –controlled 122-pt Phase II trial. Data from this Phase II trial supported the design of a Phase III
protocol that will rigorously test the hypothesis of OS benefit, as well as expand our understanding of
immune system response to cancer vaccines. Methods: 1200 pts will be randomized in a double-blind
fashion to three arms: PROSTVAC, PROSTVAC+GM-CSF, or Placebo, at 1:1:1 ratio. A five-month treatment
regimen will include a priming vaccination with PROSTVAC-V, and six booster vaccinations with
PROSTVAC-F. Eligible pts will have asymptomatic or minimally symptomatic mCRPC, and progression
despite androgen ablation and be chemotherapy-naïve. Pts with rapidly progressing disease will be
excluded, as well as pts with risk factors for developing vaccinia-associated complications. The projected trial
size is 400 pts per arm for at least 85% power. Primary endpoint is OS. The final analyses will be eventdriven and will compare each active arm independently with placebo. Pts will be followed for 12 months after
the projected number of events in each arm is realized. Secondary endpoint is proportion of event-free pts at
6 months compared to placebo. A number of exploratory endpoints are planned, including immune response
to immunizing antigen, non-vaccine-contained prostate antigens, tumor-associated antigens; changes in
baseline biomarker levels and CTC levels, as well as characterization of T cell subpopulations. The thorough
immune monitoring program would provide basis for future studies on the effects of cancer immunotherapy
on immune system and facilitate search for potential biomarkers of such effects. The trial is currently open
for enrollment. ClinicalTrials.gov registry number: NCT00450463.
Randomized phase II clinical trial to assess MUC1 specific immune response to L-BLP25 vaccine in
addition to standard therapy in newly diagnosed high-risk prostate cancer.
Abstract No:TPS4701
Citation:
J Clin Oncol 30, 2012 (suppl; abstr TPS4701)
Author(s): Nishith K. Singh, Marijo Bilusic, Joseph W. Kim, Christopher Ryan Heery, Martin H. Falk,
Bradford J Wood, Peter A. Pinto, William L. Dahut, Aradhana Kaushal, Anna Couvillon, Myrna Rauckhorst,
Peter L. Choyke, Ismail B. Turkbey, Jane B. Trepel, Kwong Yok Tsang, Jeffrey Schlom, James L. Gulley,
Ravi A. Madan; Laboratory of Tumor Immunology and Biology and Medical Oncology Branch, National
Cancer Institute, Bethesda, MD; Medical Oncology Branch, National Cancer Institute, National Institutes of
Health, Bethesda, MD; Medical Oncology Branch, National Cancer Institute, Bethesda, MD; Merck KGaA,
Darmstadt, Germany; Department of Radiology and Imaging Sciences, National Cancer Institute, National
Institutes of Health, Bethesda, MD; Urologic Oncology Branch, Center for Cancer Research, National Cancer
Institute, National Institutes of Health, Bethesda, MD; Radiation Oncology Branch, National Cancer Institute,
Bethesda, MD; Molecular Imaging Program, CCR, NCI, NIH, Bethesda, MD; Center for Cancer Research,
National Cancer Institute, Bethesda, MD; Laboratory of Tumor Immunology and Biology, National Cancer
Institute, National Institutes of Health, Bethesda, MD; Laboratory of Tumor Immunology and Biology, Center
for Cancer Research, Bethesda, MD
Abstract:
Background: In high-risk prostate cancer, radiation therapy (RT) + androgen deprivation therapy (ADT)
improve survival. Nonetheless, 10-year disease specific mortality is about 25%. L-BLP25 is a cancer vaccine
containing the BLP25 lipopeptide that targets MUC1 tumor antigen. It may enhance immune targeting of
cells that express MUC1 (e.g. prostate cancer). In murine models, RT synergizes with vaccine-induced anticancer immunity (augments T-cell mediated cancer cytolysis, up-regulates cellular Fas and costimulatory/adhesion molecules). ADT augments T-cell trafficking to prostate. Immune response to
combining the three (L-BLP25 + RT + ADT) is not known. The current trial intends to study this immune
response to L-BLP25 + RT + ADT and compare it to RT+ADT alone. Using ELISPOT, endo-rectal MRI and
serial prostate biopsies, this trial was designed to correlate systemic immune response with changes in
tumor imaging and/or tumor microenvironment after treatment with L-BLP25. This trial may provide insight
into immune response biomarkers that are most appropriate in this setting. Methods: A randomized (1:1),
open-label, phase II trial of 42 pts is planned. Eligibility: Adult males with newly diagnosed high-risk prostate
cancer (T3 or Gleason ≥ 8 or seminal vesicle involvement or N1 or PSA>20) and HLA-A2/A3 positivity (to
allow for ELISPOT analysis). The vaccine arm will receive RT + 2-year ADT + L-BLP25. Standard arm will
receive RT + 2-year ADT. L-BLP25 vaccine schedule: biweekly X 5 starting with neo-adjuvant ADT, then 6
weekly X 4 starting with RT. A single 300mg/m2 cyclophosphamide infusion (decreases suppressor T-cells)
will be given 3 days before L-BLP25 to enhance immune response in the vaccine arm. The impact of LBLP25 + RT+ADT on MUC-1-specific systemic immune response will be determined using interval peripheral
blood ELISPOT assays. Endo-rectal coil MRI will be done before and after treatment to study prostate signal
changes for correlative and predictive analysis. MRI-UltraSound guided lesion-targeted serial prostate
biopsies will be obtained to assess immune response in tumor microenvironment. Two pts have been
enrolled.
Abiraterone
A phase Ib/II study testing the safety and efficacy of combined inhibition of the AKT/PI3K and AR
signaling pathways in castration-resistant prostate cancer: GDC-0068 or GDC-0980 with abiraterone
acetate versus abiraterone acetate.
Abstract No:TPS2616
Citation:
J Clin Oncol 30, 2012 (suppl; abstr TPS2616)
Author(s): Roel Peter Funke, Jin Zhu, Raymond D. Meng, Yibing Yan, Luna C. Musib, Craig Charles Talluto,
Premal H. Patel; Genentech, South San Francisco, CA
Abstract:
Background: Loss of PTEN, leading to activation of the AKT/PI3K pathway is frequent and associated with
poor prognosis in prostate cancer. In addition, AR and AKT/PI3K cross-regulate by reciprocal feedback and
combined inhibition of both pathways resulted in improved preclinical efficacy. This study is designed to
evaluate the effect of combined inhibition of AR pathway (with abiraterone) and AKT/PI3K pathway (with
either GDC-0068 or GDC-0980). GDC-0068 is a potent, selective ATP-competitive inhibitor of AKT1, 2, and
3. Preclinical studies showed that cell and tumor models with PTEN loss are more likely to be sensitive to
GDC-0068. GDC-0068 was generally well tolerated in phase I and a MTD of 600 mg daily was identified.
GDC-0980 is a potent pan-inhibitor of Class I PI3K and inhibits wild-type and mutated p110α isoforms, as
well as mTOR kinase. The recommended phase II dose (RP2D) for single-agent GDC-0980 is 40 mg daily.
Methods: This study will enroll CRPC patients previously treated with docetaxel. In phase Ib, the RP2D will
be determined separately for GDC-0068 and GDC-0980 in combination with abiraterone 1000 mg qd and
prednisone 5mg bid. In phase II, patients will be randomized 1:1:1 to receive GDC-0068 + abiraterone, GDC0980 + abiraterone, or placebo + abiraterone. The primary endpoint of phase II is PFS measured by PCWG2
in all patients and in patients with PTEN loss. Secondary endpoints include OS, PSA response rate, ORR,
safety, Pharmacokinetics and biomarker analyses. The effect of each treatment on the number of circulating
tumor cells will be assessed. Primary and secondary analyses will include all randomized patients and will be
conducted according to assigned treatment arm. Kaplan-Meier methodology will be used to estimate median
PFS for each arm. Up to 24 patients are planned to be enrolled in phase Ib; 240 patients (80 per arm) are
planned for phase II. This study is open for accrual; to date 2 patients have been enrolled in phase Ib.
Cytoreduction and androgen signaling modulation by abiraterone acetate (AA) plus leuprolide
acetate (LHRHa) versus LHRHa in localized high-risk prostate cancer (PCa): Preliminary results of a
randomized preoperative study.
Abstract No:4556
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4556)
Author(s): Eleni Efstathiou, John W. Davis, Patricia Troncoso, Mark Anton Titus, Anh Hoang, Sijin Wen,
Amado J. Zurita, Namphuong Tran, Arturo Molina, Christopher Logothetis; University of Athens, Athens,
Greece; University of Texas M. D. Anderson Cancer Center, Houston, TX; University of Texas M. D.
Anderson Cancer Center, Houston, TX; Roswell Park Cancer Institute, Buffalo, NY; Janssen Research &
Development, Los Angeles, CA
Abstract:
Background: Endocrine to “intracrine” androgen signaling transition, a milestone in the lethal progression of
PCa, has not been characterized in localized high risk disease. Signaling heterogeneity under the selective
pressure of castration may account for response differences. Methods: A single institution preoperative
study of 12 weeks AA 1g/prednisone 5 mg + LHRHa compared to LHRHa (randomized 2:1) was conducted
in patients (pts) with high risk PCa (clinical stage ≥T1c and biopsy Gleason score ≥8, or ≥T2b, Gleason ≥ 7
and PSA > 10ng/ml). Primary aim: Assess difference in down staging (≤ ypT2) and safety. Secondary aims:
Assess difference in androgen biosynthesis, androgen signaling (AR, AR variants, NKX 3.1, ERG, PSA)
proliferation apoptosis and candidate treatment resistance pathways. Results: We report on 37 (50 enrolled)
pts who had prostatectomy. AA+LHRHa was given to 25pts, LHRHa to 12. Median age is 61 ys (46-74).
Preoperative PSA was <0.1ng/ml in 17/25 (68%) AA+LHRHa vs 0/12 LHRHa (p 0.0001). ypT2N0 occurred in
15/25 (60%) AA+LHRHa treated pts vs 4/12 (33%) LHRHa (p 0.17). Near complete cytoreduction (<6mm
scattered cells) occurred in 6/25 (24%) AA+LHRHa vs 1/12 (8%) LHRHa. Lymph node infiltration in 7/25
(28%) AA+LHRHa vs 6/12 (50%) LHRHa. Margin positivity in 2/25 (8%) AA+LHRHa vs 4/12 (33%) LHRHa (p
0.07). Grade 3 AA related AEs: elevated AST/ALT 4 (discontinued AA), hypertension 3. One AA+LHRHa pt
had postop pulmonary embolism. Androgen signaling and proliferation suppression is more profound in
AA+LHRHa treated remaining tumor cells (Table). Conclusions: Addition of AA to LHRHa results in greater
cytoreduction, suppression of PSA and androgen signaling compared to LHRHa in high risk PCa. Findings
support the hypothesis that intracrine androgen signaling is a therapy target in patients with untreated PCa
and form the foundation for a marker driven treatment strategy.
Mean tumor expression (involvement)% by IHC (standard deviation).
Marker
AA+LHRHa
LHRHa
P value Wilcoxon
AR
0.0001
27 (26)
69 (22.3)
Nkx3.1
0.002
50 (29.8)
83 (14.3)
CYP17
0.13
64 (22)
75 (14.4)
Ki67
0.003
3.4 (5)
8.6 (5.7)
Exploratory analysis of survival benefit and prior docetaxel (D) treatment in COU-AA-301, a phase III
study of abiraterone acetate (AA) plus prednisone (P) in metastatic castration-resistant prostate
cancer (mCRPC).
Abstract No:4558
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4558)
Author(s): Oscar B. Goodman, Kim N. Chi, Arturo Molina, Christopher Logothetis, Robert J. Jones, John
Staffurth, Scott A. North, Nicholas J. Vogelzang, Fred Saad, Paul N. Mainwaring, Stephen John Harland,
Jinhui Li, Thian San Kheoh, Christopher M. Haqq, Howard I. Scher, Karim Fizazi; National Cancer Institute,
Las Vegas, NV; British Columbia Cancer Agency, Vancouver, BC, Canada; Janssen Research &
Development, Los Angeles, CA; University of Texas M. D. Anderson Cancer Center, Houston, TX; Institute
of Cancer Sciences, Glasgow, United Kingdom; Cardiff University, Velindre Hospital, Cardiff, United
Kingdom; Cross Cancer Institute, Edmonton, AB, Canada; Comprehensive Cancer Centers of Nevada and
US Oncology Research, Las Vegas, NV; University of Montreal, Montreal, QC, Canada; Haematology and
Oncology Clinics of Australasia, Brisbane, Australia; UCL Cancer Institute, London, United Kingdom;
Janssen Research & Development, Raritan, NJ; Genomic Systems, San Francisco, CA; Memorial SloanKettering Cancer Center, New York, NY; Institut Gustave Roussy, Villejuif, France
Abstract:
Background: AA, a selective androgen biosynthesis inhibitor, blocks the action of CYP17, thereby inhibiting
adrenal and intratumoral androgen production. AA has demonstrated improved overall survival (OS) by 4.6
months (mos) vs placebo (HR=0.74) in patients (pts) previously treated with D. Methods: COU-AA-301 is a
randomized double blind study of AA (1 g) + P (5 mg po BID) vs placebo + P administered to mCRPC pts
post-D with a primary endpoint of OS. To further evaluate primary survival result robustness, we performed
post hoc exploratory analyses to assess whether the timing of first and last dose of D and reason for D
discontinuation impacted OS. Results: At randomization, treatment arms were balanced with respect to
baseline characteristics, prior D use, and reasons for discontinuation. In both arms, almost half (45%)
discontinued D due to progressive disease (PD); remainder discontinued D after completing all planned
cycles (37%), due to toxicity (12%), or for other reasons (5%) per investigator. Median OS from first and last
dose of D were longer with AA vs placebo (Table). Median OS was longer with AA vs placebo in pts who
discontinued D for PD, or for all other reasons. Conclusions: These exploratory analyses suggest that the
OS benefit of AA in mCRPC was maintained when calculated from first or last dose of prior D, and whether
or not pts discontinued D for PD. Pts in AA arm of this study had a prolonged median OS of > 32 mos from
time of initial D therapy. Congruity among these analyses and lack of dependence on D timing demonstrate
robustness of the primary survival result.
Median OS, mos (95% CI)
Categorya
Time from Db
From first dose D
From last dose D
AA
(N=797)
Placebo
(N=398)
32.6 (30.7, 35.0) 27.6 (25.9, 30.3)
HR = 0.75 (0.65, 0.88); p=0.0002
23.2 (22.4, 24.5) 19.4 (17.5, 20.8)
HR = 0.74 (0.64, 0.86); p ≤0.0001
Reason for D discontinuationc
PD
14.2 (12.0, 15.8) 10.5 (9.3, 11.8)
HR = 0.77 (0.62, 0.97); p=0.0222
All other reasons
17.0 (15.6, 18.2) 12.6 (10.4, 14.9)
HR = 0.73 (0.59, 0.89); p=0.0025
aInvestigator
reported (limited source verification); bcalculated from first or last dose of D; ccalculated from
randomization.
Durable radiologic and clinical disease stability beyond PSA progression in patients with metastatic
castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA).
Abstract No:4553
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4553)
Author(s): Diletta Bianchini, Shahneen Kaur Sandhu, Amy Mulick Cassidy, Andrea Zivi, Janusz Mezynski,
Deborah Mukherji, Carmel Jo Pezaro, Alison Helen Reid, Nikhil Babu Oommen, David Olmos, Aurelius
Gabriel Omlin, Ajit Sarvadikar, Emilda Thompson, Joanne Hunt, Elizabeth Sheridan, Gerhardt Attard,
Johann Sebastian De Bono; The Royal Marsden Hospital and The Institute of Cancer Research, Sutton,
United Kingdom; The Institute of Cancer Research and Royal Marsden Foundation Trust, Sutton, United
Kingdom; The Institute of Cancer Research, Sutton, United Kingdom; The Institute for Cancer Research and
Royal Marsden Hospital, Sutton, United Kingdom; Royal Marsden Hospital, Dublin, Ireland; The Institute of
Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, United Kingdom; Royal Marsden NHS
Foundation Trust, London, United Kingdom; Royal Marsden Hospital and Institute of Cancer Research,
Sutton, United Kingdom; Institute of Cancer Research, London, United Kingdom; The Royal Marsden
Hospital, Sutton, United Kingdom; The Institute for Cancer Research and Royal Marsden Foundation Trust,
Sutton, United Kingdom
Abstract:
Background: AA, a potent oral CYP17A1 inhibitor is approved for treatment of mCRPC with a survival
advantage of 4.9 months. In clinical practice, response evaluation remains challenging for pts with mCRPC.
CTC conversion from CTC ≥ 5 to CTC < 5 with treatment predicts for improved overall survival in mCRPC.
We hypothesized that pts continue to have durable disease stability beyond PSA progression on AA.
Methods: Prostate Specific Antigen (PSA) responses, radiological responses and CTC conversion rates
were retrospectively analysed in pts treated on AA at our institution. CTCs, PSA and imaging were obtained
at predefined time points during these studies. Radiological and PSA progression were defined by standard
Prostate Cancer Working Group Criteria II. Clinical progression consisted of worsening disease related pain,
skeletal events or declining performance status.Pearson’s chi-squared test and the Kaplan-Meier method
were used for this analysis. Results: 141 patients [ECOG Performance Status 0-2; Median Age: 69.7 (range
44.7-87.1); 85 post-docetaxel, 56 pre-docetaxel] received AA. The median duration of clinical and
radiological stable disease (SD) was 16.8 months (n=55) and 5.6 months (n=75) in patients with a baseline
CTCs count of ≤ 5 cells/7.5mls and ≥ 5 cells/7.5 mls respectively. In the 105 patients with documented PSA
progression on AA there was a median 5.7-month delay in detecting radiological and/or clinical progression
(95% CI: 4.2, 8.4; range 0.3, 35.6 months). Radiological and clinical SD of ≥ 1 year, ≥ 2 years and ≥ 3 years
on AA was observed in 43/141 (30.5%), 21/141 (14.9%) and 12/141 (8.5%) respectively. Conclusions:
Radiological and clinical disease stabilization beyond PSA progression is maintained in a high proportion of
mCRPC patients treated with AA. Future studies should evaluate whether continued AA treatment beyond
PSA and radiological progression can impact outcome.
Abiraterone in patients with metastatic castration-resistant prostate cancer progressing after
docetaxel and MDV3100.
Abstract No:4554
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4554)
Author(s): Ecaterina Ileana, Yohann Loriot, Laurence Albiges, Christophe Massard, Aurore Blesius, Mario Di
Palma, Bernard J. Escudier, Pierre Blanchard, Alberto Bossi, Karim Fizazi; Institut Gustave Roussy, Villejuif,
France; Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France; Medical Oncology
Department, Institut Gustave Roussy, Villejuif, France
Abstract:
Background: Chemotherapy with docetaxel is the standard first-line treatment in patients with metastatic
castration-resistant prostate cancer (mCRPC). In patients progressing after docetaxel, both abiraterone and
MDV3100 have yielded improved survival for patients with mCRPC. The efficacy of abiraterone in patients
pre-treated with MDV 3100 is unknown. Methods: We investigated abiraterone-prednisone in 24 patients
with cancer progression after docetaxel followed by MDV3100. All patients received abiraterone 1000
mg/day plus prednisone 10mg/day. Prostate-specific antigen (PSA) response, symptom response, and time
to progression were assessed. Results: Patient characteristics were as follows: median age: 74 years (5384), median PSA: 108 ng/mL (2-2541), metastatic sites: bone: all 24 patients, liver/lung: 6 patients (25%),
and lymph nodes : 9 patients (38%). Five patients (21%) had a PSA decrease on abiraterone-prednisone.
Three patients (13%) achieved a PSA response, defined as a decrease of >50% in PSA, confirmed after≥ 4
weeks. The duration of PSA response was 2, 3 and 4.5 months. Six patients (29%) had a symptomatic
response on the pain score and analgesic consumption was decreased. Treatment was well tolerated.
Abiraterone-prednisone was discontinued in one patient due to edema and hypokaliemia. Conclusions:
This study shows preliminary evidence that abiraterone-prednisone yields activity in patients with mCRPC
pretreated with docetaxel and MDV3100.
Risk of mineralocorticoid excess syndrome with CYP17 inhibitor abiraterone in prostate cancer
patients.
Abstract No:e15140
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15140)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Sandy Ann Itwaru, Arun Gopal, Omer Bashir, Joomee Shim, Xiaolei Zhu, Shenhong Wu; Stony
Brook University School of Medicine, Stony Brook, NY; Kidney Doctors PLLC, Port Jefferson Station, NY;
Stony Brook University School of Medicine, Stonybrook, NY
Abstract:
Background: CYP17 inhibitor abiraterone acetate has been used for the treatment of patients with
metastatic castration-refractory prostate cancer (CRPC). Hypertension, hypokalemia and edema are the
major side effects associated with its use, and may be secondary to the excess of mineralocorticoids due to
CYP17 inhibition. We performed a systematic review and meta-analysis of published clinical trials to
determine the effect of abiraterone on the development of these side effects. Methods: Databases including
Pubmed (July, 1966 to July, 2011), Web of Science, and abstracts presented at the American Society of
Clinical Oncology meetings from 2008 to 2011 were searched to identify relevant studies. Eligible studies
were prospective clinical trials of patients with prostate cancer receiving abiraterone acetate at the starting
dose of 1,000 mg daily with available data on hypertension, hypokalemia and edema. Incidence and relative
risk (RR) were calculated using a random-effects or fixed-effects model. Results: A total of seven studies
including 1,387 patients with CRPC were selected for analysis. The incidences of all-grade hypertension,
hypokalemia, and edema were 13.3% (95% CI: 8.3 to 20.5%), 31.4 % (95% CI: 12.5-59.5%), and 23.4 %
(95% CI: 15.6-33.5%) respectively. The incidences of high-grade (grade 3 and above) toxicity were low, with
a rate of 3.6% (95% CI: 2.6-5.1%), 2.8 % (95% CI: 0.9 to 8.2%), and 2.1% (95%CI: 1.3-3.2%) for
hypertension, hypokalemia, and edema respectively. The risk of hypertension and edema did not change
with and without the addition of prednisone (p=0.48 and p=0.40, respectively); however, the risk of
hypokalemia was significantly reduced with the addition of prednisone (p = 0.003). In comparison with
prednisone alone, the addition of abiraterone did not increase the risk of hypertension (RR 1.22, 95% CI:
0.82 – 1.83, p=0.31), but significantly increased the risk of edema (RR 1.36, 95% CI: 1.10-1.69, p=0.004)
and hypokalemia (RR 2.04, 95% CI: 1.42–2.92, p<0.001). Conclusions: There were differential effects of
abiraterone on the development of hypertension, hypokalemia, and edema in patients with advanced
prostate cancer. Further studies are recommended for optimal treatment.
Cost-effectiveness evaluation of abiraterone in the treatment of patients with castration-resistant
prostate cancer who previously received docetaxel.
Abstract No:e15107
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15107)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Akhil Chopra, Stefan Gluck, Alberto J. Montero, Kiran Kumar Venkata Raja Avancha, Gilberto
Lopes; Johns Hopkins Singapore International Medical Center, Singapore, Singapore; University of
Miami/Sylvester Comprehensive Cancer Center, Miami, FL; University of Miami Sylvester Comprehensive
Cancer Center, Miami, FL; University of Miami Hospital and Clinics/ Sylvester Comprehensive Cancer
Center, Miami, FL; Johns Hopkins Singapore, Singapore, Singapore
Abstract:
Background: Treatment with abiraterone improves overall survival (OS), time to prostate-specific antigen
progression and radiologic progression-free survival when added to prednisone and best supportive care in
patients with advanced castrate-resistant prostate cancer (CRPC) who previously received docetaxel. Little
is known about its cost-effectiveness in the United States. Methods: In order to raise awareness of
pharmacoeconomics concepts and inform policy-makers in the US, this study aimed to assess the costeffectiveness of abiraterone in the treatment of advanced CRPC patients, from a payer perspective. We
created a decision-analytical model using clinical data from the pivotal phase III trial: COU-AA-301. Health
utilities were derived from the available literature. Costs for drug acquisition, physician visits and laboratory
tests were obtained from the Center for Medicare Services Drug Payment Table and Physician Fee
Schedule and are represented in 2011 US dollars. Life-years saved (LY), Quality-adjusted life years (QALY)
and Incremental Cost Effectiveness Ratio (ICER) were calculated using updated survival data presented at
the 2011 ASCO meeting. Other main scenarios used the original median survival data published in the New
England Journal of Medicine article and adjusted median OS to represent an overall survival hazard ratio of
.66. Sensitivity analyses were performed using the confidence intervals for median OS in the pivotal study as
well as by halving or doubling all other model inputs. No discounting was used due to the short time-horizon.
Results: Abiraterone added 0.38 LY and 0.30 QALY with an incremental cost of $39,320 and therefore a
cost of $102,600/LY and an ICER of $129,000/QALY. The main drivers of the model were drug acquisition
cost, median OS, and health utility values. The results of the model were robust in different scenarios and
sensitivity analyses. Conclusions: Using commonly accepted willingness-to-pay thresholds, such as those
suggested by the World Health Organization, treatment of patients with advanced CRPC patients with
abiraterone is likely to be cost-effective in the US.
Assessment of abiraterone (ABI) tumor cell activity via in vitro models of androgen (A)-responsive
prostate cancer.
Abstract No:e15166
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15166)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Ian Hickson, Ann Marien, Maarten Derks, Marc Janssen; Janssen Pharmaceutical Companies of
Johnson & Johnson, Beerse, Belgium
Abstract:
Background: Inhibition of CYP17 by abiraterone acetate (AA) blocks A biosynthesis, reduces A levels and
results in inhibition of A-dependent tumor growth. AA has been shown to improve survival in patients with
metastatic castrate-resistant prostate cancer (HR = 0.74) (Scher, ASCO 2011). AA is converted to ABI in
vivo. This study investigates whether direct effects of ABI on tumor cells (ie, blockade of intratumoral A
synthesis) may contribute to the clinical efficacy of AA using in vitro models. Methods: LNCaP cells (human
prostate cancer cell line [HPCCL]) were grown in 2D and 3D cultures, and ABI activity was assessed by
reduction of androgen receptor (AR) output in gene expression profiling (Affymetrix microarray), reporter
assay, and by immunoblot for A-responsive signals. Using ABI-sensitive LNCaP cells, responses were
further characterized in the presence or absence of ligand (dihydrotestosterone [DHT]) and with A-targeting
agents TOK-001 and MDV3100. Results: ABI exposure resulted in dose-dependent modulation of Adependent gene expression in Affymetrix microarray analysis of 2D and 3D cultures. Similar results were
seen in an analysis of AR-dependent protein and in an AR-driven reporter assay in 2D LNCaP or VCaP
(another HPCCL) cell culture. In LNCaP, AR output was inhibited by low concentrations of ABI (IC 50 100-300
nM), comparable to TOK-001 (IC50 30-100 nM) and less potent than MDV3100 (IC50 10-30 nM). Growth
inhibition (MTT assay) occurred at concentrations 10-fold higher for all compounds. For ABI and TOK-001,
inhibition of AR output was reduced by DHT (30- to 100-fold increase in IC50); with MDV3100, the shift in IC50
was less (10-fold) with agonism of AR output at low nM concentrations. Conclusions: ABI has an inhibitory
effect on AR output in LNCaP cells. Partially overcoming this inhibition through addition of DHT implies that
CYP17 inhibition and the subsequent A reduction play a role in the intratumoral activity of AA. However,
persistent inhibition of AR output in the presence of DHT implies additional anti-A effects of AA in prostate
tumor cells. This model may provide a useful tool for the study of AR-targeted therapies, combinations of
agents, and resistance to agents targeting A.
Efficacy of abiraterone acetate in the treatment of castration-resistant prostate cancer: Early results
from the German compassionate-use program.
Abstract No:e15195
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15195)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Carsten Henning Ohlmann, Michael Stöckle, David A. Pfister, Axel Heidenreich, Axel S.
Merseburger, Markus Kuczyk, Lukas Manka, Peter Hammerer, Peter Albers, Christian Arsov, Margitta Retz,
Jürgen E. Gschwend, Susan Feyerabend, Arnulf Stenzl, Severine Banek, Jan Marin, Jochen Gleissner,
Manfred Wirth, Stefan Zastrow, Matthias Heck; Department of Urology, Saarland University, Homburg,
Germany; RWTH Aachen University, Aachen, Germany; Medical School Hannover, Hannover, Germany;
Academic Hospital Braunschweig, Braunschweig, Germany; Department of Urology, Heinrich-HeineUniversity, Duesseldorf, Germany; Department of Urology, Rechts der Isar Medical Center, Technische
Universität München, Munich, Germany; Department of Urology, Eberhard-Karls University Tuebingen,
Tuebingen, Germany; Urologie Kempen, Kempen, Germany; Urologie in der Hofaue, Wuppertal, Germany;
University Hospital Carl Gustav Carus, Dresden, Germany
Abstract:
Background: Abiraterone acetate (AA) plus prednisone (P) has demonstrated an improved survival of
patients with castration-resistant prostate cancer (CRPC) compared to placebo plus P in a large phase III
trial. In Germany, patients were able to receive AA within a compassionate-use program (CUP). Here, we
report the first results of the program. Methods: Patients were eligible for the CUP if they progressed on or
after at least one cytotoxic chemotherapy regimens. For CUP entry, patients were considered to have
disease progression if they had radiographic evidence of disease progression in soft tissue or bone with or
without PSA-progression and ongoing androgen deprivation. Patients received AA 1000mg daily plus
prednisone 5mg BID until progression of disease or unacceptable toxicity. Results: Between 02-05/2011,
398 patients were registered for the CUP in Germany. Data from 191/350 (47.9%) of the patients treated at
10 different sites were available for evaluation of efficacy. Median age was 70.72yrs (52.35-87.61) and
patients received a median of 1 (1-4) chemotherapy lines prior to CUP entry. Median PSA at baseline was
220.5 ng/ml (0.47-4245); 168 (88%) of patients presented with bone metastasis. With regard to efficacy,
64/191 (33.5%) of the patients showed an unconfirmed PSA-response ≥50%. At a median follow-up of 5.3
months, 51/191 (26.7%) patients had died, resulting in a median PSA-progression free and overall survival of
8.3 and 10.61 months, respectively. In a subset of patients (71/191, 37.2%) data regarding objective
response was available with 25/71 (35.2%) achieving an objective response. Data from 114 pts. revealed
fatigue (20.3%), hot flushes (15.8%), edema (10.6%), elevated liver enzymes (8.0%) and asthenia (7.9%)
being the most frequent toxicities (any grade). Conclusions: Treatment of CRPC patients with AA outside
controlled clinical trials leads to considerable PSA- and objective response rates with a favourable toxicity
profile, comparable to the results from COU-AA-301 registration trial. Due to the short median follow-up,
conclusions regarding PSA-progression free and overall survival may not be drawn.
Sarcopenia and altered body composition following abiraterone acetate (AA) and corticosteroid (C)
treatment in men with castration-refractory prostate cancer (CRPC).
Abstract No:e15134
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15134)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Deborah Mukherji, Carmel Jo Pezaro, Diletta Bianchini, Nina Tunariu, Amy Mulick Cassidy,
Aurelius Gabriel Omlin, Shahneen Kaur Sandhu, Gerhardt Attard, Johann Sebastian De Bono; The Institute
of Cancer Research and Royal Marsden Foundation Trust, Sutton, United Kingdom; The Institute of Cancer
Research, Sutton, United Kingdom
Abstract:
Background: Sarcopenia, or skeletal muscle wasting, is an independent prognostic factor in advanced
malignancy (Prado Lancet Onc 2008). Decreased muscle and increased fat are recognized side effects of
androgen deprivation therapy. AA is a CYP17 inhibitor administered with corticosteroids (C), approved for
treatment of advanced CRPC. AA reduces circulating androgens to ‘super-castrate’ levels; we hypothesized
that AA + C would impact body composition. Methods: We retrospectively evaluated 54 CRPC pts treated
on a Phase I/II trial. Pts received AA alone followed by combination AA + C on biochemical progression. CT
scans at baseline, on AA alone and on AA + C were analyzed. Cross-sectional areas of fat and muscle were
measured on 3 consecutive images at L4 using OsiriX 4.0. Muscle area was used to calculate skeletal
muscle index (SMI); sarcopenia was defined as SMI <52.4 cm 2/m2. Data were analyzed using t-tests and
Kaplan-Meier analysis with overall survival (OS) measured from day 1 of AA. Results: Median duration on
AA alone was 7.4 months (m; range 1.4-37.5); median duration on concurrent AA + C was 7.4m (range 0.946.2). Body composition did not change between two pre-treatment scans (n=29; median 3m apart). On AA
alone there was a decrease in total fat (-8.5%, p=0.0001), visceral fat (-9.8%, p=0.0015) and muscle mass (3.9%, p=0.0023) with a significant decrease in mean body mass index (BMI; -3.4 %, p=0.0118). Conversely
AA + C was associated with increased total fat (+15.1%, p<0.0001) and visceral fat (+21.4%, p<0.0001) but
no further change in muscle mass. Mean BMI significantly increased on the addition of C, returning to
baseline levels (p< 0.0001). Overall, 13 pts (24%) were sarcopenic prior to commencing AA compared to 22
(41%) at the end of treatment. Pts who were sarcopenic at baseline had significantly reduced OS: 26.1m
(95%CI 16.6 – 41) vs 46.5m (95%CI 28.6 – 57.5, p=0.0253). Conclusions: Treatment with AA alone
resulted in decreased fat and muscle. AA + C increased body fat without further alteration in muscle mass.
Changes in BMI did not reflect changes in body composition. Sarcopenia at baseline was a negative
prognostic factor in this population.
Effects of 6 months of abiraterone acetate (AA) on muscle and adipose mass in men with metastatic
castration-resistant prostate cancer (mCRPC).
Abstract No:e15137
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15137)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Samuel Craig Brondfield, Vivian K. Weinberg, Kathryn M. Koepfgen, Arturo Molina, Charles J.
Ryan, Eric Jay Small, Andrea Lynne Harzstark; University of California, San Francisco, San Francisco, CA;
OrthoBiotech Oncology Research and Development, Los Angeles, CA
Abstract:
Background: AA, an inhibitor of androgen biosynthesis, has been shown to prolong overall survival in
patients with mCRPC who have previously been treated with chemotherapy. ADT has been shown to result
in muscle wasting in prostate cancer patients. The effects of AA on progression of muscle and fat wasting
have not been characterized. We evaluated whether 6 months of AA therapy altered total skeletal muscle
mass or adipose mass. Methods: 10 sequential patients who responded to AA therapy for at least 6 months
and had available computed tomography (CT) scans were retrospectively selected from the phase I-II COUAA-002 study. CT image analysis was used to quantify change from baseline in total skeletal muscle and
adipose tissue after 6 months of AA treatment. Skeletal muscle and adipose tissue cross-sectional area were
calculated at the L3 level using Slice-O-Matic software V4.3. Previously published regression models were
used to estimate fat-free mass, fat mass and skeletal muscle mass. Paired t-tests were performed to
determine the change in measurements. Results: At baseline, 7 of 10 patients were overweight or obese
(body mass index [BMI] > 25 kg/m 2), and none were underweight. Advanced muscle wasting (sarcopenia,
previously defined as the ratio of skeletal muscle cross-sectional area at L3 level to height < 52.4 cm 2/m2)
was present at baseline and 6 months in 9 of 10 pts. Over 6 months of AA treatment, patients lost an
average of 1.9 kg ± 3.6 kg (p = 0.13). Mean changes (kg) (±standard deviation) in total skeletal muscle mass
(-0.80 ± 1.71, p = 0.18) and total non-adipose mass (-1.44 ± 3.09, p = 0.17) were not significant. A significant
decrease in total adipose mass (-0.61 ± 0.84, p = 0.048) was observed. Conclusions: Sarcopenia is
prevalent in patients with mCRPC. AA was not related to significantly worsening sarcopenia or overall weight
loss during the first 6 months of treatment; however, this may reflect a relatively short duration of therapy
and/or small sample size. A significant loss of adipose tissue was observed, which is unexpected given the
known effects of ADT, which increases adipose mass. Evaluation of additional AA treated patients is
ongoing.
Inhibition of 3β-hydroxysteroid dehydrogenase by abiraterone: A rationale for increasing drug
exposure in castration-resistant prostate cancer.
Abstract No:4645
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4645)
Author(s): Nima Sharifi, Rui Li, Kristen Evaul, Kamalesh Sharma, Richard J Auchus; University of Texas
Southwestern Medical Center, Dallas, TX; University of Michigan, Ann Arbor, MI
Abstract:
Background: Treatment with abiraterone acetate (abi) increases the survival of men with castrationresistant prostate cancer (CRPC). Resistance to abi invariably occurs, probably due in part to up-regulation
of steroidogenic enzymes and/or other mechanisms that sustain the synthesis of dihydrotestosterone (DHT),
which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic
enzymes. The 1,000 mg daily abi dose was selected for the phase III trials despite the absence of doselimiting toxicities at higher doses. Based on the 3β-hydroxyl, Δ5-structure, we hypothesized that abi also
inhibits 3β-hydroxysteroid dehydrogenase/isomerase (3βHSD), which is absolutely required for the
intratumoral synthesis of DHT in CRPC, regardless of origins or routes of synthesis. Methods: We tested if
abi inhibits recombinant 3βHSD2 activity in vitro or endogenous 3βHSD activity in LNCaP and LAPC4 cells,
including conversion of [3H]-dehydroepiandrosterone (DHEA) to androstenedione (AD), androgen receptor
(AR) nuclear translocation, expression of AR-responsive genes, and LAPC4 xenograft growth in
orchiectomized mice supplemented with DHEA. Results: Abi has a mixed inhibition pattern of 3βHSD2 in
vitro, blocks the conversion from DHEA to AD and DHT with an IC 50 of < 1 µM in CRPC cell lines, inhibits AR
nuclear translocation and expression of TMPRSS2, and decreases CRPC xenograft growth in DHEAsupplemented mice. Conclusions: Abi blocks 3βHSD enzymatic activity, synthesis of AD and DHT, inhibits
the AR-response, and suppresses growth of CRPC cells at concentrations that are clinically achievable.
Variable abi inhibition of 3βHSD might account in part for the heterogeneous clinical response to abi. More
importantly, 3βHSD inhibition with abi might be clinically harnessed to reverse resistance to CYP17A1
inhibition at the standard dose by dose-escalation, or simply by administration with food to increase drug
exposure.
Response to ketoconazole (keto) or docetaxel (D) following clinical progression on abiraterone
acetate (AA) in castrate-resistant prostate cancer (CRPC).
Abstract No:4664
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4664)
Author(s): Rahul Raj Aggarwal, Carl Formaker, Eric Jay Small, Arturo Molina, Charles J. Ryan; University of
California, San Francisco, San Francisco, CA; OrthoBiotech Oncology Research and Development, Los
Angeles, CA
Abstract:
Background: Patients (pts) with CRPC treated with keto often experience a rise in serum adrenal androgen
levels upon progression and may subsequently respond to more potent adrenal suppression with AA. In
contrast, pts treated with AA do not have a rise in serum androgen levels upon progression, and thus may
not respond to further androgen synthesis inhibition with keto but require other treatment modalities such as
chemotherapy instead. The goal of this analysis is to report the outcomes of pts with CRPC progressing on
AA subsequently treated with either keto or D. Methods: Pts with chemotherapy-naïve CRPC were treated
on previously reported phase 1 and 2 trials of AA, with doses ranging from 250 to 1000 mg/day. Subsequent
treatment following progression on AA was per individual investigator discretion, including treatment with
either keto or D. Results: To date, following disease progression on AA, 6 and 14 pts have been
subsequently treated with either keto or D respectively. Of the 14 pts treated with D, 11 (79%) had exposure
to keto prior to AA. The keto- and D-treated cohorts were similar with respect to other baseline factors,
including prior response to AA (4/6 (67%) pts with > 50% PSA decline on AA in keto cohort; 10/14 (71%) pts
in D cohort); though pts treated with D were more likely to require opioid analgesics (0 pts in keto cohort; 7
(50%) in D). For pts treated with keto, none experienced a decline in PSA, improvement in bone scan, or an
objective response; all had disease progression by 12 weeks. In contrast, for pts treated with D, 10 (71%)
had a decline in PSA; 6 (43%) with a > 50% maximum PSA decline. Of 6 pts with measurable disease, 2
(33%) had an objective response. The median time to progression for the D cohort was 129 days (range 60
– 294). Conclusions: Although the cohort size is small, and post-AA therapy was not randomized, these
data provide preliminary support for the hypothesis that CRPC progressing on AA is cross-resistant to further
androgen synthesis inhibition with keto. Contrary to other reports, prior treatment with AA does not appear to
decrease the likelihood of subsequent response to D, but this observation requires prospective validation.
Cabazitaxel
Updated safety result of a large Italian early access program (EAP) with cabazitaxel plus prednisone
(CbzP) in metastatic castration-resistant prostate cancer (mCRPC) patients who progressed during
or after docetaxel (D) therapy.
Abstract No:e15185
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15185)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Sergio Bracarda, Giuseppe Di Lorenzo, Donatello Gasparro, Paolo Marchetti, Francesco
Boccardo, Andrea Martoni, Giacomo Carteni, Giuseppe Fornarini, Valentina Baldazzi, Luigi Dogliotti,
Caterina Messina, Michele Sisani; Presidio Ospedaliero San Donato, Arezzo, Italy; Department of Oncology,
University of Federico II of Napoli, Napoli, Italy; Medical Oncology, Parma, Italy; Oncology Department,
Azienda Ospedaliera S. Andrea, Roma, Italy; Oncology Department, Istituto Nazionale per la Ricerca sul
Cancro, Genova, Italy; Medical Oncology, S. Orsola-Malpighi Hospital, Bologna, Italy; Oncology, Cardarelli,
Napoli, Italy; Ospedale San Martino, Genoa, Italy; Oncologia Medica 2, Università degli Studi di Firenze,
Firenze, Italy; Ospedale San Luigi Gonzaga, Orbassano, Italy; Ospedali Riuniti di Bergamo, Bergamo, Italy;
Medical Oncology, Arezzo, Italy
Abstract:
Background: A significant percentage of mCRPC pts, who have progressed on D therapy, have a long life
expectancy and are candidates for additional treatments. In TROPIC trial pts who progressed during or after
D had a statistically significant OS advantage and clinical benefit with CbzP in respect to mitoxantrone plus
prednisone (MP). Benefits observed in the TROPIC study supported a global EAP, to allow pts with mCRPC
to have an early access to CbzP and provide confirmatory data in daily clinical practice Methods: We report
the safety results of the first 90 pts entered into EAP and treated with CbzP, out of 232 pts enrolled by 25
Italian centers between Jan and Aug 2011 Results: Pts characteristics were median age 70 years (≥ 75
years 22.2%); ECOG PS 0-1, 97.8%; median N. of previous D cycles 8 (median cumulative D 675mg/m 2);
14.1% received 675 ÷ 900 mg and 40.0% ≥ 900 mg of D. Median time from last D dose to first CbzP dose
was 5.29 months including any other chemotherapy treatment.At the time of this analysis 50% of pts had
received 4 cycles of CbzP. 33 pts discontinued CbzP mainly due to PD (42.4%), AEs (related/not related,
27.3%), investigator’s (3.0 %) / pts decision (18.2%) and others (9.1%). AEs resulting in CbzP
discontinuation (10.0%) are mainly fatigue, pyrexia and haematological disorders. A total of 57 pts were still
on treatment. In the 33 discontinued pts, CbzP has been delayed in 24.2% while a dose reduction occurred
in 21.2% of pts. AEs of any grade were observed in 81/90 pts. Most common G 3/4 AEs were leukopenia
(25.6%), neutropenia (48.9%), anaemia (6.7%), diarrhoea (1.1%), asthenia (3.3%) and fatigue (5.6%). One
death occurred during the study period in a heavily pretreated pt who received 33 cycles of D Conclusions:
This preliminary safety analysis suggests the good tolerability of cabazitaxel, in terms of haematological as
well as non-haematological AEs even in heavily pretreated pts according to the previous experience of
Italian Centers in theTROPIC trial. This is remarkable because of the increased similarity of the patient’
populations treated in the EAP and daily clinical practice
Safety data of cabazitaxel in patients treated for metastatic castration-resistant prostate cancer after
docetaxel treatment: Results of a cohort of patients during the temporary authorization for use in
France (ATU).
Abstract No:e15142
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15142)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Nadine Houede, Jean-Christophe Eymard, Zoubir Tahar; Institut Bergonié, Bordeaux, France;
Institut Jean Godinot, Reims, France; Sanofi, Paris, France
Abstract:
Background: The TROPIC (Johann Sebastien de Bono et al ; Lancet 2010) study demonstrated that
cabazitaxel (a novel tubulin-binding taxane drug) improves overall survival of patients (pts) with mCRPC who
progressed during or after docetaxel-based chemotherapy, with a median survival of 15.1 months. Based on
this result, a compassionate-use program has been established to provide pts with mCRPC the opportunity
to receive the treatment, before licensing of the drug. Methods: ATU of cabazitaxel in France has been
granted before its marketing authorization; all safety data from pts treated during this period were collected
following a specific therapeutic use protocol. All participating physicians were instructed about the molecule
by a company physician and contacted before the first treatment, on day 15 and at the end of treatment of
each patient to make sure that all G3/4 and serious adverse events were collected. Results: We report
baseline characteristics and safety data from the 184 pts treated in 92 French centers. Median age was 67.2
years (46 - 92), ECOG performance status was 0-1 for 85% of pts, 88% had bone metastases and 21% had
visceral metastases. All the pts had received prior docetaxel, 55% had discontinued for disease progression;
85% of the pts received previously 1-2 lines of chemotherapy. Pts received a median of 3 cycles of
cabazitaxel (1-6). Rates of grade 3-4 hematological toxicities were: neutropenia grade≥ 3 (4%), febrile
neutropenia (3%), all resolved. All grade other toxicities were: nausea (0.5%), diarrhea (2.7%) and fatigue
(0.5%). No treatment-related death was reported. Conclusions: The ATU program provides additional
safety information on cabazitaxel in the real-life setting; they are consistent with the TROPIC study safety
results. The incidence of neutropenia grade≥ 3 (4%) and febrile neutropenia (3%) appears to be lower than
expected. Therapeutic use protocols such as these can be helpful for physicians when new therapies
become available. Proactive education of healthcare givers on AEs management could be considered when
new treatments are introduced.
Evaluation of the response to cabazitaxel of a docetaxel-responsive hormone-refractory prostate
tumor xenograft model (HID28).
Abstract No:e15161
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15161)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Ludovic Bourre, Delphine Nicolle, Marie-Emmanuelle Legrier, Vanessa Yvonnet, Julie
Charpentier, Marie-France Poupon, Patricia Vrignaud, Christine Geffriaud-Ricouard, Stephane Oudard,
Jean-Gabriel Judde; Xentech, Evry, France; Sanofi, Paris, France; Hôpital Européen Georges Pompidou,
Paris, France
Abstract:
Background: Docetaxel was the first cytotoxic treatment demonstrating a survival benefit in metastatic
castration-resistant prostate cancer (mCRPC) patients. Recently, cabazitaxel (a novel taxane) and
abiraterone acetate (specific inhibitor of CYP17) have demonstrated a significant survival benefit in mCRPC
patients progressing after receiving a docetaxel – containing regimen. Here we compare the antitumor
efficacy of docetaxel, cabazitaxel and abiraterone acetate in the HID28 hormone-refractory human prostate
carcinoma xenograft. Methods: HID28 tumor bearing nude mice received 20 mg/kg of docetaxel (IP, q3wk x
2), cabazitaxel at 15 and 20 mg/kg (IP, q3wk x 2) and abiraterone acetate at 50 mg/kg (PO, qdx21). Median
tumor growth inhibition (T/C%) was evaluated as well as time course androgen receptor expression (4, 8 and
24h post dosing) by western blot analysis. Results: Docetaxel (20 mg/kg) inhibited tumor growth with a
T/C%= 16.7% at D35, 2 partial (PR) and 1 complete (CR) tumor regressions, and with relapse of all tumors
(6/6) observed at D42. Cabazitaxel demonstrated dose-dependent efficacy at D35 with T/C%= 10.8% and
1.4% for 15 and 20 mg/kg doses respectively. At a cabazitaxel dose of 15 mg/kg, 4/10 PR and 3/10 CR were
observed, whereas 4/10 PR and 6/10 CR were observed at 20 mg/kg. At D42, 6/6 tumor relapses were
observed at 15 mg/kg; whereas, only 3/6 relapses were observed at 20 mg/kg. No anti-tumor activity was
demonstrated with abiraterone acetate as well as no significant decreases in testosterone levels compared
to the vehicle group. Tolerability was good for all treatment groups, with a transitory maximum mean body
weight loss of 12%, 6 days after treatments. Androgen receptor western blot expression analysis after 4, 8
and 24h post dosing demonstrated no significant difference between groups and over time. Conclusions:
Cabazitaxel and docetaxel showed similar tolerability at equivalent dose levels. Cabazitaxel demonstrated
superior antitumor efficacy over docetaxel at equivalent dosing in the HID28 hormone-refractory tumor
model. These results support the clinical development of cabazitaxel in first line treatment of mCRPC
patients.
A cohort compassionate-use program with cabazitaxel plus prednisone for patients with metastatic
castration-resistant prostate cancer: Interim results.
Abstract No:e15112
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15112)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Sevil E. Bavbek, Zafar I Malik, Giuseppe Di Lorenzo, Hans-Jorg Scholz, Inge M van Oort, Siobhan
Ng, Mustafa Ozguroglu, Winald R. Gerritsen, Stefan Mueller, Timo Marttila, Luis M. Antón Aparicio, Peter
Albers, Jürgen E. Gschwend, Samira Bensfia, Evelyne B Ecstein-Fraïssé, Sergio Bracarda, Axel
Heidenreich; Istanbul University Oncology Institute, Istanbul, Turkey; Clatterbridge Centre for Oncology,
Wirral, United Kingdom; Genitourinary Cancers Section, AOU Federico II, Napoli, Italy; Asklepios Klinik
GmbH, Weißenfels, Germany; Radboud University Nijmegen Medical Center, Nijmegen, Netherlands;
Bendat Cancer Centre, Subiaco, Australia; Cerrahpasa Medical Faculty, Istanbul University, Istanbul,
Turkey; Department of Medical Oncology, Amsterdam, Netherlands; University Hospital Bonn, Bonn,
Germany; Seinajoki Central Hospital, Seinajoki, Finland; CHUA Coruña, Servico de Oncologia, A Coruña,
Spain; Department of Urology, Duesseldorf, Germany; Technical University of Munich, Munich, Germany;
Sanofi, Paris, France; Department of Medical Oncology, USL-8 Istituto Toscano Tumori, Arezzo, Italy;
Department of Urology, RWTH University, Aachen, Germany
Abstract:
Background: In the TROPIC trial (NCT00417079), treatment with CbzP produced a statistically significant
improvement in overall survival vs mitoxantrone + prednisone (MP) in patients (pts) with mCRPC previously
treated with a docetaxel (D)-containing regimen (HR 0.70; p< 0.0001). These results supported the
establishment of 2 programs (based on local regulations): a compassionate use (CUP) and an early access
program (EAP; NCT01254279). Methods: The aims of the CUP/EAP are to provide drug to pts with mCRPC
who may benefit from CbzP prior to commercial availability and further assess CbzP safety profile. Total
enrollment for both programs is estimated at 1600 pts from 250 centers globally. Eligible pts receive CbzP
(25 mg/m2 Q3W + prednisone 10 mg PO QD) until disease progression, death, unacceptable toxicity or
physician/pt decision. Results: Baseline characteristics and safety data are available for the first 399 pts:
median age was 68 yrs (range 43–89), with 90.2% ECOG PS 0–1. The median cumulative dose of prior D
was 675 mg/m2; prior therapy with MP was permitted. For pts whose disease progressed following D,
median time from last dose of D to progression was 4 months; 53.3% of pts experienced disease
progression either during or < 3 months after D. 61% of pts had ≥ 2 metastatic sites; the most common were
bone (93.2%) and regional lymph nodes (34.4%). At the time of analysis, a median of 4 cycles of CbzP had
been administered; 4 pts received ≥ 10 cycles. Median relative dose intensity was 99.2% (range 80.1–
104.9). G-CSF was administered to 34.3% of pts in Cycle 1 (6.3% therapeutic, 26.6% prophylactic). Overall,
71.4% of pts had adverse events (AEs; all grades). Most common grade 3-4 AEs were neutropenia 11.3%,
febrile neutropenia 6.3%, anemia 2.8%, fatigue 2%, neutropenic sepsis 1.8%, vomiting 1.3% and diarrhea
1%. Eight (2%) treatment-related deaths were reported. Conclusions: The CUP/EAP provides additional
safety data for CbzP in a routine clinical practice pt population with heavily pre-treated mCRPC. Treatment
with CbzP was tolerable, with a predictable and manageable toxicity profile consistent with data reported for
TROPIC and the product labeling.
Comparison of two doses of cabazitaxel plus prednisone in patients (pts) with metastatic castrationresistant prostate cancer (mCRPC) previously treated with a docetaxel (D)-containing regimen.
Abstract No:
TPS4692^
Citation:
J Clin Oncol 30, 2012 (suppl; abstr TPS4692^)
Author(s): Mario A. Eisenberger, Anne-Claire Hardy-Bessard, Loic Mourey, Paul N. Mainwaring, Daniel Ford,
Jeremy David Shapiro, Joan Carles, Siobhan Ng, Thierry Gil, Boris Alekseev, Sergey Ivanov, Thomas
Facchini, Eric Legouffe, Oleg Apolikhin, Hardev S. Pandha, Aart Beeker, Oleg Karyakin, Wendy Zhang,
Mustapha Chadjaa, Johann Sebastian De Bono; Sidney Kimmel Comprehensive Cancer Center at Johns
Hopkins University, James Buchanan Brady Urological Institute, Baltimore, MD; Clinique Armoricaine de
Radiologie, Service D'Oncologie Medicale, Saint Brieuc, France; Institut Claudius Regaud, Service
D'Oncologie Medicale, Toulouse, France; Mater Private Centre for Haematology and Oncology, Brisbane,
Australia; City Hospital, Birmingham, United Kingdom; Cabrini Medical Centre, Melbourne, Australia;
University Hospital Vall d'Hebron, Barcelona, Spain; Bendat Cancer Centre, Subiaco, Australia; Institut Jules
Bordet, Université Libre de Bruxelles, Brussels, Belgium; Hertzen Moscow Oncology Research Institute,
Moscow, Russia; Scientific Center for X-ray Radiology, Moscow, Russia; Clinique de Courlancy, Reims,
France; Centre Medical Oncogard, Clinique Valdegour, Nimes, France; Scientific Research Institute of
Urology, Moscow, Russia; Postgraduate Medical School, University of Surrey, Guildford, United Kingdom;
Spaarne Ziekenhuis, Hoofddorp, Netherlands; Medical Radiological Research Center, Obninsk, Russia;
Sanofi, Malvern, PA; Sanofi, Paris, France; The Royal Marsden NHS Foundation Trust and The Institute of
Cancer Research, Sutton, United Kingdom
Abstract:
Background: The phase III TROPIC study (NCT00417079) reported a significant improvement in overall
survival (OS) for cabazitaxel (Cbz) + prednisone (P;CbzP) (25 mg/m 2 IV Q3W/10 mg PO QD) vs
mitoxantrone (M) + P (MP) (median OS 15.1 vs 12.7 mos; HR 0.70; P < 0.0001) in pts with mCRPC (also
known as hormone-refractory prostate cancer) previously treated with a D-containing regimen. CbzP is
approved by the FDA, EMA and other health authorities for the treatment of pts with mCRPC that has
progressed after a D-containing regimen. Cbz toxicity is consistent with other taxanes; compared with M,
more hematologic toxicities are reported (primarily Grade 3–4 neutropenia). Phase I/II studies identified 20
and 25 mg/m2 as recommended doses; 25 mg/m 2 was selected for the phase III TROPIC study. As pooled
data show Grade 3–4 neutropenia incidence is lower with Cbz < 25 mg/m 2 (61%) vs ≥ 25 mg/m 2 (74%), it is
of interest to assess if reducing the Cbz approved dose in mCRPC lessens hematologic toxicity and is noninferior in terms of efficacy. Methods: PROSELICA (NCT01308580) is a randomized, open-label,
multinational, phase III study comparing 20 mg/m 2 and 25 mg/m2 Cbz for efficacy and tolerability. Pts with a
life expectancy > 6 mos, ECOG PS ≤ 2, histologically/cytologically confirmed metastatic prostate
adenocarcinoma resistant to hormone therapy and previously treated with a D-containing regimen are
eligible. Pts are randomized 1:1 to receive Cbz 20 mg/m² or 25 mg/m² IV Q3W + P 10 mg PO QD, treated
until disease progression, unacceptable toxicity or withdrawal of consent (max 10 cycles), and stratified
according to ECOG PS, measurable disease (yes/no) and region. The primary endpoint is OS (non-inferiority
design). Secondary endpoints include safety, progression-free survival (PCWG2 criteria), PSA and pain
progression and response, tumor response in pts with measurable disease and health-related quality of life.
Cbz PK and pharmacogenomics will be assessed in pt subgroups. Planned enrollment is 1,200 pts. Study
start was in May 2011; as of Jan 2012, 270 pts had been enrolled. The first DMC meeting recommended
continuing the study without change.
First-line use of cabazitaxel in chemotherapy-naive patients with metastatic castration-resistant
prostate cancer (mCRPC): A three-arm study in comparison with docetaxel.
Abstract No:
TPS4696^
Citation:
J Clin Oncol 30, 2012 (suppl; abstr TPS4696^)
Author(s): Stephane Oudard, Lisa Sengelov, Paul N. Mainwaring, Antoine Thiery- Vuillemin, Christine
Theodore, Evgeny Kulikov, Jeffrey Yachnin, Ivo Kocak, Vesa V Kataja, Marjaana Luukkaa, Aleander Nosov,
Marie Hjelm-Eriksson, Jeffrey Bubis, Liji Shen, Marie-Laure Risse, A. Oliver Sartor; Georges Pompidou
European Hospital, Paris, France; Department of Oncology, Herlev, Denmark; Mater Private Centre for
Haematology and Oncology, Brisbane, Australia; Medical Oncology Unit, Besancon, France; Hospital Foch,
Suresnes, France; Regional Clinical Oncology Dispensary, Ryazan, Russia; Department of Oncology,
University Hospital Uppsala, Uppsala, Sweden; Masarykuv Onkologicky Ustav, Brno, Czech Republic;
Cancer Center, Kuopio University Hospital, Kuopio, Finland; Department of Oncology and Radiotherapy,
Turku University Hospital, Turku, Finland; N. N. Petrov Research Institute of Oncology, Saint Petersburg,
Russia; Department of Oncology-Pathology, Stockholm, Sweden; Cancer Specialists of North Florida,
Jacksonville, FL; Sanofi, Malvern, PA; Sanofi, Paris, France; Tulane Medical School, New Orleans, LA
Abstract:
Background: Docetaxel (D) in combination with prednisone (P) as first-line (1L) chemotherapy in patients
(pts) with mCRPC is the current standard of care. However, treatment is not curative and D-resistant disease
typically develops. Cabazitaxel (Cbz) is a novel taxane active in D-sensitive and -resistant tumor models.
Clinical activity of Cbz plus P (CbzP) was demonstrated in the Phase III TROPIC study in mCRPC pts
previously treated with a D-containing regimen; CbzP showed a significant overall survival (OS) benefit vs
mitoxantrone plus prednisone (median OS 15.1 vs 12.7 months; HR 0.70; P < 0.0001). Therefore, it is of
interest to determine if CbzP provides an OS advantage vs DP in 1L mCRPC pts. Methods: The phase III
FIRSTANA study (NCT01308567) is a randomized, open-label, multinational trial in 1L mCRPC pts,
designed to compare the efficacy of Cbz 25 mg/m² IV Q3W (Arm A) and Cbz 20 mg/m² IV Q3W (Arm B) vs D
75 mg/m2 IV Q3W (Arm C). P 10 mg PO QD is to be given concomitantly. Pts are stratified by ECOG PS (0–
1 vs 2), measurable disease (yes/no) and region (depending on availability of Cbz as 2L). Pts with ECOG PS
≤ 2, histologically/cytologically confirmed metastatic prostate adenocarcinoma, with no prior chemotherapy
and with disease progression following medical or surgical castration are eligible. The primary endpoint is
OS. Secondary endpoints include progression-free survival (PFS) (PCWG2 criteria), radiologic PFS, tumor
response in measurable disease (RECIST 1.1), PSA response and PSA PFS, pain response and pain PFS,
time to occurrence of any skeletal-related events, safety profile and health-related quality of life. Cbz
pharmacokinetics and pharmacogenomics will be assessed in pt subgroups. Pts will be treated until
progression, unacceptable toxicity or pt request. Planned enrollment is 1,170 pts; study size was calculated
to achieve 90% power for OS. Study start was in May 2011; at January 2012, 219 pts were enrolled. The first
DMC meeting recommended continuing the study without change.
Sipuleucel-T
Evaluation of immune activation following neoadjuvant sipuleucel-T in subjects with localized
prostate cancer.
Abstract No:2563
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 2563)
Author(s): Nadeem A. Sheikh, Johnna D. Wesley, Nikole Perdue, Frances P. Stewart, Lawrence Fong;
Dendreon Corporation, Seattle, WA; University of California, San Francisco, San Francisco, CA
Abstract:
Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy for men with
asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). NeoACT
(Study P07-1) was undertaken to investigate neoadjuvant sipuleucel-T treatment in subjects with localized
prostate cancer. Methods: In this open-label, phase 2 study (NCT00715104), subjects with localized
prostate cancer received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7 weeks
prior to radical prostatectomy (RP). Following RP, subjects were randomized 1:1 to receive / not receive a
sipuleucel-T booster infusion 12 weeks post-RP. Cellular composition, antigen presenting cell (APC)
activation, cytokines, and T and B cell activation were profiled before and after each culture with PA2024, the
fusion protein containing prostatic acid phosphatase used to generate sipuleucel-T. Results: Of the 42
enrolled subjects (median age: 61 years; 98% Caucasian), 38 received all 3 infusions of sipuleucel-T, and 15
subjects received a booster infusion. Consistent with sipuleucel-T in mCRPC, CD54 upregulation (APC
activation) was greater at the second and third infusions relative to the first (p<0.001). The expression of
early T cell activation markers (CD134, CD137, CD278 and CD279) were increased in pre-culture cells
obtained after the first infusion, and further increased after culture. Activated mature B cells
(CD20+CD27+IgD+CD86+) increased following culture in all 3 products (p<0.01); memory B cells
(CD20+CD27+IgD-CD86+) were progressively increased following the first infusion (p<0.05 third vs. first
product). TNF-α, IFN-γ, IL-2 were secreted at higher levels during culture of the second and third products
(all p<0.001). The observed increases in CD54 upregulation, early T cell activation markers, and memory
and activated mature B cells were maintained at booster treatment. Conclusions: Neoadjuvant sipuleucel-T
resulted in robust immune system activation that was consistent with boosting of an immune response
primed with the first infusion. Immune activation was maintained at the booster infusion 3 months following
initial sipuleucel-T treatment.
Neoadjuvant sipuleucel-T in localized prostate cancer: Effects on immune cells within the prostate
tumor microenvironment.
Abstract No:2564
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 2564)
Author(s): Lawrence Fong, Vivian K. Weinberg, Stephen E Chan, John M Corman, Christopher L Amling,
Robert A Stephenson, Carl Formaker, Jeffrey Simko, Robert Brownell Sims, Peter Carroll, Eric Jay Small;
University of California, San Francisco, San Francisco, CA; Virginia Mason Medical Center, Seattle, WA;
Oregon Health & Science University, Portland, OR; University of Utah, Salt Lake City, UT; Dendreon
Corporation, Seattle, WA
Abstract:
Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy for patients with
asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). To date,
studies of sipuleucel-T in patients with mCRPC have studied immune response in peripheral blood. The
effects of sipuleucel-T on prostate tumors are unknown. Methods: NeoACT (P07-1; NCT00715104) is an
open-label, phase 2 study of patients with localized prostate cancer who received sipuleucel-T prior to
radical prostatectomy (RP) to examine the immunologic effects of treatment on prostate tissue. Patients
received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6-7 weeks prior to RP. The
primary endpoint was the change in the frequency of lymphocytes between prostate biopsies (pre-treatment)
and RP tissue (post-treatment), as assessed by immunohistochemistry (IHC). Results: The median age of
the 42 enrolled patients was 61 years, and all had an ECOG performance status of 0. Thirty-eight patients
received all 3 pre-RP sipuleucel-T infusions. To date, tissue IHC analysis has been completed on 32
patients. Treatment-related AEs were manageable and transient. Sipuleucel-T did not appear to impact
surgery, as judged by operative complications, procedure time, and estimated blood loss. Frequent events
that occurred ≤1 day after infusion (>10% of patients) were fatigue, headache, and myalgia. Significant
increases (≥3 fold) in CD3+ and CD4+ T cell populations were observed at the tumor interface (where benign
and malignant glands interface), compared with the pre-treatment biopsy, benign RP tissue, and tumor RP
tissue (ANOVA post hoc Newman-Keuls test: p<0.0001 for each comparison). FoxP3+ CD4+ T cells were
also increased (p=0.0005) at the tumor interface, but represented a small fraction of the observed CD4+ T
cells. Conclusions: Neoadjuvant sipuleucel-T treatment is associated with an increased frequency of T cells
in prostate cancer tissue at the interface of the benign and malignant glands. These data suggest that
sipuleucel-T can modulate the presence of lymphocytes at the prostate tumor site. Work is ongoing to more
fully characterize the immune response.
Initial experience with sipuleucel-T (sip-T) in the immediate post-approval setting: The University of
Washington (UW) experience.
Abstract No:e15206
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15206)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): James P. Dean, Evan Y. Yu, Suzanne Beauchene, Suzanne P Hall, Celestia S. Higano; Fred
Hutchinson Cancer Research Center, Seattle, WA; University of Washngton and Seatlle Cancer Care
Alliance, Seattle, WA; Seattle Cancer Care Alliance, Seattle, WA; University of Washington, Seattle, WA
Abstract:
Background: UW has participated in clinical trials of sip-T for over 15 years. After sip-T administration in the
3 phase III trials, patients (pts) did not receive additional therapy until objective progression. However, the
course of treatment after administration of sip-T outside the setting of a clinical trial is not defined. In order to
better understand our own practices in response to this new clinical scenario, we evaluated our institutional
experience with commercial sip-T after FDA approval. Methods: Charts of all pts treated with sip-T at UW
with at least 3 mos follow-up were retrospectively reviewed. Pt characteristics and treatments administered
during the first 3 mos after sip-T infusion were collected. The institutional review board approved this study.
Results: Between June 2010 and Nov 2011, 36 pts with mCRPC were treated with commercial sip-T by 3
different MDs. There were 31 Caucasian, 3 African American, and 2 Asian pts. At diagnosis, Gleason score
(# pts) was 3+3 (2), 3+4 (5), 4+3 (7), 4+4 (4), 4+5 (16), 5+5 (2); initial therapy was watchful waiting (1), ADT
with brachytherapy [BT] (1), BT with XRT (4), ADT/XRT (6), radical prostatectomy [RP] (9), ADT/RP (1). At
the time of sip-T therapy, median age 67.8 yrs (44.2 to 84.5), median PSA 56.0, LDH 179.5, alk phos 77,
Hgb 12.7, CTC 2. 3 pts had prior chemotherapy for metastatic disease. 34, 2, and 1 pts received 3, 2, and 1
sip-T infusion(s) respectively. Within the first 3 mos after the last sip-T dose, 29 pts had no significant
symptoms and received no additional therapy other than ADT +/- ongoing zoledronic acid or denosumab
(27), ketoconazole (1), or nilutamide (1); 7 developed pain and received docetaxel [D] (1), XRT and D (3),
XRT (1), nilutatmide/D (1), or cabozantinib (1). 6 pts died a median of 10 months after sip-T; none had
received chemotherapy before sip-T therapy. Conclusions: The majority of UW pts (80%) received no
additional therapy in the first 3 mos after sip-T while 20% developed pain and were treated with docetaxel or
other systemic therapy. What treatments should be given and at what interval after sip-T remains unclear. It
is likely that new agents will impact the treatment paradigm after sip-T.
Impact of salvage therapy with APC8015F on the overall survival (OS) benefit achieved with
sipuleucel-T in three phase III studies of metastatic castrate-resistant prostate cancer (mCRPC).
Abstract No:e15120
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15120)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Leonard G. Gomella, Chadi Nabhan, Todd DeVries, James Boyd Whitmore, Mark Walter Frohlich,
Daniel J. George; Jefferson Kimmel Cancer Center, Philadelphia, PA; Advocate Lutheran General Hospital
and Oncology Specialists, S.C., Park Ridge, IL; Dendreon Corporation, Seattle, WA; Duke University Medical
Center, Durham, NC
Abstract:
Background: Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic or minimally
symptomatic mCRPC. Three phase III sipuleucel-T trials (D9901, D9902A and D9902B [IMPACT]) allowed
control patients (pts) to receive salvage treatment with an autologous product derived from previously frozen
cells (APC8015F). We previously reported that salvage therapy with APC8015F demonstrated no deleterious
effect and may have improved outcomes in control pts, potentially reducing the observed survival benefit
seen with sipuleucel-T. Thus, we performed an exploratory analysis of pooled data from phase III studies to
estimate the impact of APC8015F treatment on the OS benefit conferred by sipuleucel-T. Methods: We
analyzed the effect of salvage APC8015F therapy on OS, and used a rank-preserving structural failure time
(RPSFT) model to estimate control arm OS if treatment with APC8015F had not occurred. This allows
estimation of the effect of sipuleucel-T treatment on OS, adjusting for salvage effect. Results: Median OS
from randomization in the three pooled trials was 25.4 months with sipuleucel-T (n=488) and 21.5 months
with control (n=249). Of the control arm pts, 165 (66.3%) subsequently received APC8015F. Median OS
from randomization in the control population was 23.6 months for pts receiving APC8015F and 12.7 months
for those who did not. Using the RPSFT model, and assuming APC8015F was as effective as sipuleucel-T,
the estimate of median OS for control pts was 17.3 months, representing an 8.1 month median increase in
OS with sipuleucel-T. Results from extensions of the RPSFT model, where APC8015F is assumed to have
less treatment effect than sipuleucel-T, will be presented. Conclusions: These analyses estimated a median
OS benefit for sipuleucel-T between 3.9 and 8.1 months, assuming that APC8015F had either no efficacy or
comparable efficacy to sipuleucel-T, respectively. The results suggest a possible greater treatment effect of
sipuleucel-T than was reported in the three phase III studies. Future studies should account for potential
crossover treatment bias as this may diminish estimates of OS benefit.
Sipuleucel-T immunotherapy in clinical practice: Patient characteristics, tolerability, and survival.
Abstract No:e15211
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15211)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Matthew O'Shaughnessy, Christopher Warlick, Matthew Ziegelmann, Badrinath Konety, Gautam
Gopalji Jha; University of Minnesota, Minneapolis, MN
Abstract:
Background: Sipuleucel-T has been shown to provide survival benefit to men with minimally symptomatic
metastatic castration-resistant prostate cancer (mCRPC). In the 18 months following FDA approval of
sipuleucel-T, we sought to characterize patients referred for consideration of sipuleucel-T, determine the
tolerability of therapy, and evaluate survival outcomes in clinical practice. Methods: We reviewed the
records of patients referred to our institution for consideration of sipuleucel-T. Clinical characteristics,
disease characteristics, and previous treatments were identified. Tolerability and adverse events were
characterized. Results: Patients with minimally symptomatic mCRPC were offered sipuleucel-T (n=90),
whereas patients with ECOG>1, progressive disease, or lack of metastases were not (n=11). Post
chemotherapy patients started sipuleucel-T if their CD4 count was >400 at least 3 weeks following
chemotherapy. Treatments were well tolerated, with 96% completing an entire series. Three patients did not
complete treatment due to disease progression. The biggest challenge with sipuleucel-T therapy was
disease control immediately before, during and post therapy. Androgen receptor blockade with nilutamide or
high dose bicalutamide was used to control the disease during this time. Mean patient age was 69.8±9.7
years and all had ECOG status of 0-1. 40% of patients had minimal metastases, while 36% and 19% had
moderate or extensive metastases. Median survival time (MST) for men >65 years who received sipuleucelT was 17.6 months, whereas MST for men ≤65 years was not reached. There was no significant difference in
overall survival (OS) between these groups (p=0.27). When stratified by disease burden, we found that OS
of patients with extensive disease was shorter than men with mild or moderate disease burden (p=0.002 and
p=0.04), with MST of 6.0 months. MST was not reached for men with mild and moderate disease burden.
Conclusions: Sipuleucel-T is well tolerated in clinical practice for well-selected patients with asymptomatic
or minimally symptomatic mCRPC. Patients with extensive metastatic disease, even when minimally
symptomatic, did not appear to benefit from sipuleucel-T.
Overall survival (OS) benefit with sipuleucel-T by baseline PSA: An exploratory analysis from the
phase III IMPACT trial.
Abstract No:4648
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4648)
Author(s): Gerald Chodak, Paul F. Schellhammer, James Boyd Whitmore, Robert Brownell Sims, Philip W.
Kantoff; Weiss Memorial Hospital, Chicago, IL; Eastern Virginia Medical School/Urology of Virginia, Norfolk,
VA; Dendreon Corporation, Seattle, WA; Dana-Farber Cancer Institute, Boston, MA
Abstract:
Background: Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic or minimally
symptomatic metastatic castrate-resistant prostate cancer. In the IMPACT trial, sipuleucel-T showed a 22.5%
reduction in risk of death vs the control group (hazard ratio [HR]=0.775 [95% CI 0.614, 0.979]; P=0.032). A
pre-specified subgroup analysis for baseline prognostic variables showed homogeneous treatment effects
consistently favoring sipuleucel-T. In patients (pts) with baseline PSA below vs above the median, there was
a trend toward greater treatment effect (HR=0.685 vs. 0.865). In this exploratory analysis, we further subdivide baseline PSA into quartiles to evaluate potential treatment effect patterns. Methods: The analysis
included all randomized pts from IMPACT (n=512). Pts were categorized by baseline PSA quartile (Table),
ECOG PS and by median for other baseline prognostic variables (i.e., LDH, PAP, ALP in bone-only disease,
and Hgb). Median OS and HR were estimated using Kaplan-Meier and Cox models, respectively. Results:
Increasing baseline PSA quartile was associated with markers of advanced disease. HRs suggest a
consistent treatment effect in all subsets, although there is inadequate power to show significant results
within each quartile. There was a trend toward an increased magnitude of treatment benefit in pts with a
lower baseline PSA (Table). Results for other baseline prognostic variables also suggest a trend toward
greater benefit in subjects with better prognostic features. However, results for baseline Hgb indicated an
opposite trend. Conclusions: Although not adequately powered for significance, the results of this analysis
support a consistent OS benefit with sipuleucel-T across PSA quartiles. The greater magnitude of benefit in
pts with lower baseline PSA suggests that pts with less advanced disease may benefit more from treatment
with sipuleucel-T.
Baseline PSA (ng/mL)
≤22.1
n
Median OS, months
Sipuleucel-T
Control
Difference
HR (95% CI)
128
>22.1–50.1
128
>50.1–134.1
128
>134.1
128
41.3
28.3
13.0
0.51 (0.31, 0.85)
27.1
20.1
7.1
0.74 (0.47, 1.17)
20.4
15.0
5.4
0.81 (0.52, 1.24)
18.4
15.6
2.8
0.84 (0.55, 1.29)
Correlation of increased eosinophil count following sipuleucel-T treatment with outcome in patients
(pts) with metastatic castrate-resistant prostate cancer (mCRPC).
Abstract No:4650
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4650)
Author(s): Douglas G. McNeel, Daniel W. Lin, Thomas Gardner, Nadeem A. Sheikh, James Boyd Whitmore,
Robert Brownell Sims, Robert Dreicer; University of Wisconsin-Madison, Madison, WI; University of
Washington, Seattle, WA; Indiana University School of Medicine, Indianapolis, IN; Dendreon Corporation,
Seattle, WA; Cleveland Clinic, Cleveland, OH
Abstract:
Background: Sipuleucel-T is the first autologous cellular immunotherapy approved for asymptomatic or
minimally symptomatic mCRPC. In the IMPACT trial, pts treated with sipuleucel-T had transient increases in
eosinophil counts compared with control. In this retrospective analysis, we assess potential correlations
between eosinophilia, overall survival (OS), prostate cancer-specific survival (PCSS) and immune response
following sipuleucel-T. Methods: Data from three phase III trials (D9901, D9902A, and IMPACT) were
pooled. The analysis included CBCs performed at baseline and wks 2–34. Eosinophilia was defined as either
>ULN (with normal baseline), or a max change from baseline within the top quartile, at any time between wks
2–16. Results: Increased eosinophil counts were seen in sipuleucel-T pts by wk 6, decreasing to near
baseline by wk 14; eosinophil counts in control pts were stable. Of 377 sipuleucel-T pts eligible for analysis,
105 (27.9%) had eosinophilia. Baseline disease characteristics associated with eosinophilia were indicative
of better prognosis (i.e., longer Halabi predicted survival [p=0.007], lower PSA [P=0.033], higher Hgb
[p<0.001], and no prior docetaxel [p=0.012]). In univariate analyses, eosinophilia correlated with improved
OS (HR=0.75; 95%CI: 0.56–1.01; p=0.057) and PCSS (HR=0.71; 95%CI: 0.53–0.97; p=0.031); trends
persisted after adjusting for Halabi. The magnitude of eosinophilia positively correlated with antigen-specific
humoral responses (p ≤0.039 for wks 6, 14 and 26) and elevations in the cytokines at wk 6 (IL2 [p=0.011],
IL5 [p=0.038] and TARC [p=0.001]). AEs occurring more frequently (p<0.05) in pts with eosinophilia were
infusion-related: pyrexia (33.3 v 21.3%) and nausea (19.0 v 10.7%). No cases of hypereosinophilic
syndrome were reported. Conclusions: Increases in eosinophils after sipuleucel-T correlated with improved
OS and PCSS. Large increases in eosinophil counts were associated with humoral responses and Th2-type
cytokine production. Further studies of eosinophilia as a biomarker for sipuleucel-T response, particularly in
earlier disease settings, are of interest.
MDV3100
TERRAIN: A randomized, double-blind, phase II study comparing MDV3100 with bicalutamide (Bic) in
men with metastatic castrate-resistant prostate cancer (CRPC).
Abstract No:TPS4698^
Citation:
J Clin Oncol 30, 2012 (suppl; abstr TPS4698^)
Author(s): Edwina S. Baskin-Bey, Neal D. Shore, Kenya Barber, Taoufik Ouatas, Axel Heidenreich; Astellas
Pharma Europe, Ltd., Staines, United Kingdom; Carolina Urologic Research Center, Myrtle Beach, SC;
Astellas Pharma Global Development, Inc., Deerfield, IL; Astellas Pharma Europe BV, Leiderdorp,
Netherlands; RWTH Aachen University, Aachen, Germany
Abstract:
Background: MDV3100 is a novel androgen receptor (AR) signaling inhibitor (ARSI) in clinical development
for treatment of prostate cancer (PCa). Compared with Bic in nonclinical CRPC models, MDV3100 showed
higher affinity AR binding, inhibited nuclear translocation and AR-DNA binding, showed no evidence of AR
agonism, and caused tumor regression in Bic-resistant xenografts. MDV3100 has shown antitumor activity in
men with advanced PCa. We present the study design of a trial comparing MDV3100 and Bic in men with
progressive metastatic PCa. Methods: Multinational study (Table) with planned enrollment of 370 patients
(randomized 1:1 to MDV3100 160 mg/d or Bic 50 mg/d). Inclusion criteria include metastatic (≥2 bone
lesions or soft tissue disease at screening) progressive CRPC (≥3 rising prostate-specific antigen [PSA]
levels or new bone/soft tissue disease), ongoing stable gonadotropin-releasing hormone (GnRH) analog
therapy or surgical castration (serum testosterone <50 ng/dL), Eastern Cooperative Oncology Group
performance status 0–1, and life expectancy ≥1 year. Exclusion criteria include previous chemotherapy,
current/prior antiandrogens (except if administered for <12 wk and discontinued no less than 6 mo before
study). Patients will be stratified by time of bilateral orchiectomy or GnRH analog initiation (before/after
diagnosis of metastases) and will receive treatment until occurrence of radiographic progression/skeletalrelated event, start of new antineoplastic therapy, or development of an adverse event requiring
discontinuation. Results: The primary endpoint is progression-free survival; secondary endpoints are safety,
PSA response, and time to PSA progression. Exploratory endpoints include circulating tumor cell conversion
rate and quality of life. Patients are currently enrolling. Conclusions: This ongoing, head-to-head, phase II
trial is the first to prospectively assess whether MDV3100 can provide improved antitumor effects vs Bic in
men with metastatic CRPC.
Country Sites, n
Canada
4
US-East
12
US-Midwest 13
US-South 11
US-West
10
Country
France
Germany
Romania
UK
Belgium
Sites, n
9
6
3
5
5
Primary, secondary, and quality-of-life endpoint results from the phase III AFFIRM study of MDV3100,
an androgen receptor signaling inhibitor.
Abstract No:4519^
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4519^)
Author(s): Johann Sebastian De Bono, Karim Fizazi, Fred Saad, Mary-Ellen Taplin, Cora N. Sternberg, Kurt
Miller, Peter Mulders, Kim N. Chi, Andrew J. Armstrong, Mohammad Hirmand, Brian Selby, Howard I. Scher,
for the AFFIRM Investigators; The Institute for Cancer Research, London, United Kingdom; University of
Paris Sud, Orsay, France; University of Montreal Hospital Center, Montreal, QC, Canada; Dana-Farber
Cancer Institute, Boston, MA; San Camillo and Forlanini Hospital, Rome, Italy; Charité-Universitätsmedizin
Berlin, Berlin, Germany; Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; Vancouver
Cancer Centre, British Columbia Cancer Agency, Vancouver, BC, Canada; Duke Cancer Institute, Duke
University Medical Center, Durham, NC; Medivation, Inc., San Francisco, CA; Memorial Sloan-Kettering
Cancer Center, New York, NY
Abstract:
Background: MDV3100, a novel androgen receptor signaling inhibitor (ARSI), inhibits: 1) binding of
androgens to AR, 2) AR nuclear translocation, and 3) association of AR with DNA. MDV3100 was active in a
phase I-II trial enrolling pre- and post-docetaxel castration-resistant prostate cancer (CRPC) patients. The
AFFIRM trial evaluated whether MDV3100 could provide benefit to men with post-docetaxel CRPC.
Methods: In this double-blind, multinational phase III study, patients who had received docetaxel-based
chemotherapy were randomized 2:1 to MDV3100 160 mg/day or placebo. Treatment with corticosteroids
was allowed but not required. Patients were stratified by baseline ECOG and mean brief pain inventory
score. The primary endpoint was overall survival (OS). Other efficacy endpoints included radiographic
progression-free survival (rPFS), time to PSA progression (TTPP), soft tissue objective response (PR+CR),
PSA response, and quality of life (QoL) response (FACT-P). Results: 800 patients were randomized to
MDV3100 and 399 to placebo with respective median treatment durations of 8.3 and 3.0 months.Based on a
planned interim analysis at 520 deaths, the Independent Data Monitoring Committee recommended the
study be unblinded and placebo patients offered MDV3100. Efficacy results are presented (Table). The most
common MDV3100 events with an incidence higher than placebo were fatigue (34% vs 29%), diarrhea (21%
vs 18%), and hot flush (20% vs 10%). Grade >3 events of interest were cardiac disorders (0.9% MDV3100
vs 2% placebo), fatigue (6% MDV3100 vs 7% placebo), seizure (0.6% MDV3100 vs. 0% placebo), and LFT
abnormalities (0.4% MDV3100 vs 0.8% placebo). Conclusions: MDV3100, a novel ARSI, is well-tolerated
and significantly prolongs OS, slows disease progression, and improves QoL in men with post-docetaxel
CRPC.
MDV3100
Placebo
HR (95% CI)
P value
OS, median 18.4 months 13.6 months 0.631 (0.529, 0.752) <0.0001
rPFS, median 8.3 months 2.9 months 0.404 (0.350, 0.466) <0.0001
TTPP, median 8.3 months 3.0 months 0.248 (0.204, 0.303) <0.0001
PR+CR
25.1%+ 3.8% 2.9%+1.0% <0.0001
PSA response 54.0%
1.5%
<0.0001
QoL response 43.3%
17.8%
<0.0001
ADT
Analysis of time to castration-resistant prostate cancer (CRPC) after initiating primary androgen
depletion therapy (PADT) of prostate cancer.
Abstract No:e15106
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15106)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Hideyuki Akaza, Shiro Hinotsu, Japan Prostate Cancer Study Group (J-CaP); Research Center for
Advanced Science and Technology, The University of Tokyo, Tokyo, Japan; Department of
Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan
Abstract:
Background: Recent clinical trials for developing new drugs for castration resistant prostate cancer (CRPC)
have been done for the patients who are surgically or medically castrated, with castration level of
testosterone. Although patients who received combined androgen blockade (CAB) with anti-androgen must
have shown PSA progression after discontinuing the anti-androgen prior to study enrollment, such patients
are analyzed together with patients with castration monotherapy. Methods: We analyzed the time to CRPC
among the patients with primary androgen depletion therapy (PADT); LH-RH agonist or CAB (LH-RH agonist
+ anti-androgen) who have registered to the J-CaP study and were followed up for >10 years. Time to CRPC
was defined as PSA progression or other disease progression. Patients were stratified into three risk groups
using JCAPRA score (JCO 2009; 26: 4309). In addition to the time to CRPC, overall survival length (OS)
after initiating PADT was analyzed. Results: Time to CRPC was significantly longer in the CAB group than
monotherapy group in intermediate and high risk groups (Table). In addition, in the intermediate and high risk
groups, OS was significantly longer for the patients with CAB (Log-rank test). Conclusions: The significant
differences of the time to CRPC and OS will influence to the outcome of clinical trials of CRPC. It is important
to take the type of ADT in to consideration when we analyze the results of clinical study of CRPC.
Risk category
Number of patients Low Intermediate High
JCAPRA score
0~2
3~7
8+
Time to CRPC (median month)
Low/Int/High
CAB (number of patients)
121
93
19
(3,552/1,803/2,057)
Low/Int/High
Monotherapy (no. of patients)
91
47
7
(2,732/1,407/670)
p (log-rank test)
p=0.45
p<0.0001 p<0.0001
Other treatments
A phase I study of TRC105 (Anti-CD105 [endoglin] antibody) in metastatic castration resistant
prostate cancer (mCRPC).
Abstract No:3043
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 3043)
Author(s): Fatima H Karzai, Andrea Borghese Apolo, David Adelberg, Ravi A. Madan, James L. Gulley,
Philip M. Arlen, Howard L. Parnes, Ann Pierpoint, David R. Kohler, Jane B. Trepel, Douglas K. Price, Seth M.
Steinberg, William Douglas Figg, William L. Dahut; Medical Oncology Branch, National Cancer Institute,
National Institutes of Health, Bethesda, MD; Laboratory of Tumor Immunology and Biology and Medical
Oncology Branch, National Cancer Institute, Bethesda, MD; Division of Cancer Prevention, National Cancer
Institute, Bethesda, MD; National Cancer Institute, Bethesda, MD; Molecular Pharmacology Section,
National Cancer Institute, National Institutes of Health, Bethesda, MD; Biostatistics and Data Management
Section, CCR, NCI, NIH, Bethesda, MD
Abstract:
Background: Pre−clinical and clinical evidence demonstrates an important role for angiogenesis in mCRPC
biology. CD105 (endoglin) is a transmembrane protein expressed on the surface of proliferating vascular
endothelial cells. The expression of CD105 is required for the formation of new blood vessels. TRC105 is a
human/murine chimeric IgG1 kappa monoclonal antibody that binds to human CD105 (endoglin). It inhibits
angiogenesis and tumor growth through inhibition of endothelial cell proliferation, antibody-dependent
cellular cytotoxicity, and induction of apoptosis. The primary objective is to evaluate safety and identify the
maximum tolerable dose (MTD) of TRC105. Secondary objectives include the assessment of TRC105
pharmacokinetics, PSA response rate, evaluation of progression free survival (PFS), overall response rate
(ORR) and overall survival (OS). Methods: Patients with an ECOG performance status (PS) ≤ 2, progressive
mCRPC and either chemotherapy-naïve or post-docetaxel treatment were eligible. Six cohorts of patients, on
escalating dose levels, receive TRC105 intravenously at doses of 1, 3, 10, 15, or 20 mg/kg IV every 2 weeks
(cohorts 1, 2, 3, 5, and 6) or 10 mg/kg IV weekly (cohort 4) on a 4 week cycle. Response is assessed with
imaging studies every 2 months for the first four months and then every 3 months thereafter. Results:
Sixteen patients are enrolled in cohorts 1-5. Median age is 65 (range 48-87), median ECOG PS is 1 (range
0−2), median Gleason score is 8 (range 6−10), median on−study PSA is 147.5 (range 0.1-3373), and
median number of prior (non-hormonal) therapies is 3 (range 0−6). Median time on study is 16 weeks (range
8-28 weeks). One patient experienced a dose limiting toxicity (grade 4 vasovagal episode) in cohort 5. PSA
declines were seen in 6 patients ranging from 20% to 57% from baseline. Ten out of 12 patients with
measurable soft tissue disease achieved stable disease for at least two cycles. Conclusions: TRC105 is
tolerated up to 15 mg/kg every two weeks with early evidence of clinical activity in mCRPC. An additional
cohort (6), with dosage of 20 mg/kg, is currently under investigation. Accrual is ongoing to evaluate ORR,
PFS, and OS in the phase II portion of this study.
Dual antiangiogenic therapy using lenalidomide and bevacizumab with docetaxel and prednisone in
patients with metastatic castration-resistant prostate cancer (mCRPC).
Abstract No:4569
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4569)
Author(s): Bamidele Adesunloye, Xuan Huang, Yangmin M. Ning, Ravi A. Madan, James L. Gulley, Melony
Beatson, Paul Gustav Kluetz, David E. Adelberg, Philip M. Arlen, Howard L. Parnes, Marcia Mulquin, Seth
M. Steinberg, John Joseph Wright, Jane B. Trepel, Nancy Ann Dawson, Clara Chen, Carol Bassim, Andrea
Borghese Apolo, William Douglas Figg, William L. Dahut; Medical Oncology Branch, National Cancer
Institute, National Institutes of Health, Bethesda, MD; U.S. Food and Drug Administration/National Cancer
Institute, Silver Spring, MD; Laboratory of Tumor Immunology and Biology and Medical Oncology Branch,
National Cancer Institute, Bethesda, MD; National Cancer Insitute, Bethesda, MD; National Cancer Institute,
Bethesda, MD; Division of Cancer Prevention, National Cancer Institute, Bethesda, MD; Metabolism Branch,
National Cancer Institute, National Institutes of Health, Bethesda, MD; Biostatistics and Data Management
Section, CCR, NCI, NIH, Bethesda, MD; National Cancer Institute, Rockville, MD; Georgetown Lombardi
Comprehensive Cancer Center, Washington, DC; Department of Nuclear Medicine, Clinical Center, National
Institutes of Health, Bethesda, MD; National Institute of Dental and Craniolfacial Research, National
Institutes of Health, Bethesda, MD; Molecular Pharmacology Section, National Cancer Institute, National
Institutes of Health, Bethesda, MD
Abstract:
Background: Previously, we had shown the potent anti−tumor activity of dual anti-angiogenic therapy by
combining bevacizumab (B) and thalidomide (T) with docetaxel (D) and prednisone (P) in mCRPC (Ning
JCO 2010). We hypothesized that combining lenalidomide (L), an analogue of T, with B, D, and P would
have a more favorable efficacy/toxicity profile. Methods: All patients (pts) had chemotherapy−naïve
mCRPC. Among the first 52 pts, 3 received L 15 mg daily, 3 had 20 mg daily, and the rest had 25 mg daily
for 14 days of every 21−day cycle (C). The protocol was recently amended to enroll 11 more pts at L 15 mg;
2 pts have now been enrolled in this expansion cohort. All pts received D 75 mg/m2 and B 15 mg/kg on day
1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. PSA each C with
imaging after C2 and after every 3C. Dental exams with mandible CT scan at baseline, after C5, and every
6C. Results: 54 of 62 pts have been enrolled. Median age 65.5 (51−82), Gleason score 8 (5−10), on−study
PSA 85.2 ng/ml (0.15−3520), and pre−study PSA doubling time 1.49 months (0.52−6.73). Median number of
Cs was 16 (3−38). PFS was 22 months and probability of survival at 12 months was 90%. Forty-six (85.2%)
and 42 (77.8%) pts had PSA declines of ≥50% and ≥75%, respectively. Of 30 pts with measurable disease
there were 1 CR and 25 PR (86.7% overall RR). 17/54 pts were off study for radiographic disease
progression and 8/54 for other reasons. Grade ≥2 toxicities included neutropenia (34/54), anemia (23/54),
thrombocytopenia (7/54), hypertension (12/54), perianal fistula (3/54), rectal fissure (1/54), myocardial
infarction (1/54), and osteonecrosis of the jaw (ONJ) (12/54, 22.0%). At the time of diagnosis of ONJ, 7/12pts
were on bisphosphonates (BP), 2/12 had used BP previously, and 3/12 never used BP. The incidence of
ONJ was comparable to 18.3% reported by Ning et al. A recent study of carboplatin plus weekly docetaxel
reported an incidence of 29.3%. Conclusions: Dual anti-angiogenic therapy with, B and L, plus D and P was
associated with high PSA (85.2%) and tumor (86.7%) responses in mCRPC, with manageable toxicities. The
incidence of ONJ is comparable to other studies.
Investigator-sponsored trial of efficacy and tolerability of cabozantinib (cabo) at lower dose: A dosefinding study in men with castration-resistant prostate cancer (CRPC) and bone metastases.
Abstract No:4566
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4566)
Author(s): Richard J. Lee, M. Dror Michaelson, Philip James Saylor, Carol Ann Gurski, Stephen M.
Rothenberg, David Tomoaki Miyamoto, Shyamala Maheswaran, Daniel A. Haber, Jonathan G. Goldin,
Matthew Raymond Smith; Massachusetts General Hospital Cancer Center, Boston, MA; Center for
Computer Vision and Imaging Biomarkers, University of California, Los Angeles, CA
Abstract:
Background: Cabo (XL184) is an oral inhibitor of MET and VEGFR2. In a randomized discontinuation trial of
cabo 100mg daily, 76% of men with CRPC and bone metastases had partial or complete resolution of bone
scan lesions as early as week (wk) 6. However, treatment was limited by adverse events (AEs), with dose
reductions in 51% of patients (pts), and discontinuations in 10%. The current study was designed to
determine the efficacy and tolerability of cabo at lower starting doses. Methods: An adaptive response
scheme was used to determine the lowest active daily cabo dose among dose levels +1 (60mg), 0 (40mg),
and -1 (20mg). The primary endpoint was wk 6 bone scan response (BSR) assessed with an automated FDA
510(k) approved computer-aided detection system. A ≥30% decrease in total bone scan lesion area (BSLA)
was defined as a response. The first cohort was treated at dose level 0. The number of responses (≥8 vs. <8
among 11 evaluable pts) was used to select the dose level (-1 vs. +1) for the second cohort. Based on the
observed BSR rate in the second cohort of 11 pts, a dose was selected for expansion to treat 13 more pts.
Results: The study completed planned enrollment of 36 pts. Median age was 66; 44% were docetaxelpretreated. Among 12 pts enrolled at dose level 0, there were 10 BSRs at wk 6 including 1 complete
response (CR), and 1 pt with stable disease (SD). The median decrease in BSLA was 62%. Ten pts
evaluated at wk 12 included 9 BSRs (3 CRs), and 1 sustained SD. Among 11 pts then treated at dose level 1, 10 pts were evaluable at wk 6: 1 BSR, 5 SD, and 4 had progressive disease. No pts in the 2 cohorts
required dose reduction or treatment interruption at 12 wks; 1 pt discontinued due to grade 3 AEs (anorexia,
fatigue). 6/12 pts with ≥6 months follow-up remain on study. 5/5 pts enrolled at 40mg with CTCs ≥5 per
7.5mL converted to <5. Thirteen pts accrued to the expansion cohort at 40mg daily had confirmed high BSR
rate. Conclusions: Cabo 40mg daily achieves a high BSR rate in men with CRPC and bone metastases,
and is associated with better tolerability than previously reported for cabo 100mg daily.
Targeting castration resistant prostate cancer (CRPC) with autologous PSMA-directed CAR+ T cells.
Abstract No:TPS4700
Citation:
J Clin Oncol 30, 2012 (suppl; abstr TPS4700)
Author(s): Susan F. Slovin, Xiuyan Wang, Oriana Borquez-Ojeda, Jolanta Stefanski, Malgorzata Olszewska,
Clare Taylor, Shirley Bartido, Howard I. Scher, Michel Sadelain, Isabelle Riviere; Sidney Kimmel Center for
Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY.
Abstract:
Background: Based on our preclinical animal models, we initiated a phase I dose-escalating study to
assess safety, dose requirement and targeting efficiency of genetically directed autologous human T cells
targeted to Prostate Specific Membrane Antigen (PSMA). Our approach is based on the infusion of
autologous PSMA-targeted T cells utilizing the P28z second generation chimeric antigen receptor (CAR) in
patients (pts) with metastatic CRPC, following iv cyclophosphamide (Cy) (trial NCT01140373). For safety,
the herpes simplex virus-1 thymidine kinase (hsvtk) gene is co-expressed with the P28z receptor, and
renders T cells sensitive to ganciclovir for immediate T cell elimination if needed. The expression of hsvtk
enables PET imaging using radiolabeled FIAU to localize adoptively transferred T cells. The aims of the trial
are to assess: (1) safety of PSMA-targeted T cells; (2) biologic and anti-tumor effects; (3) T cell persistence
at tumor site; and (4) immune response. Methods: Autologous T cells are activated from a leukapheresis
product using anti-CD3/CD28 Dynabeads. Release criteria include mean vector copy number by Q-PCR and
vector identity by Southern blot, absence of Replication Competent Retrovirus and residual Dynabeads. Pts
will be treated at 3 dose levels from 107 to 108 CAR+ T cells/kg. Four patients have been enrolled; 3 have
been treated with 300mg/m2 of Cy one day before infusion of 10 7 CAR+ T cells/kg. Pts underwent baseline
and post treatment CT, bone and PET scans. Pts are followed weekly, then monthly with blood work
including immune and vector sequence monitoring. Results: The first 3 pts within the first cohort were
successfully treated without toxicity. Two had stable disease for greater than 6 months with the third patient
having disease progression. There were no acute adverse events. Conclusion: We have established an ex
vivo transduction, expansion and therapeutic protocol for the generation and testing of safe, clinical-grade,
PSMA targeted T cells. Pts enrolled at the next dose level of 3 x 10 7 CAR+ T cells/kg will be assessed as
described and by imaging the transduced T cell population using 18F-FIAU as a radiotracer. The data
pertaining to the planned T cell imaging will be presented as well.
A phase II study of the androgen signaling inhibitor ARN-509 in patients with castration-resistant
prostate cancer (CRPC).
Abstract No:TPS4697
Citation:
J Clin Oncol 30, 2012 (suppl; abstr TPS4697)
Author(s): Dana E. Rathkopf, Neal Shore, Emmanuel S. Antonarakis, William R. Berry, Joshi J. Alumkal,
Ronald Tutrone, Mansoor N. Saleh, Charles H. Redfern, Ralph J. Hauke, Glenn Liu, Jill Elise Steinbrecher,
Daniel Costin Danila, Tracy Curley, Gabrielle Arauz, Peter J. Rix, Edna Chow Maneval, Isan Chen, Howard I.
Scher; Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center,
New York, NY; Grand Strand Urology, Myrtle Beach, SC; The Sidney Kimmel Comprehensive Cancer Center
at Johns Hopkins University, Baltimore, MD; Cancer Centers of North Carolina, Raleigh, NC; Oregon Health
& Science University Knight Cancer Institute, Portland, OR; Chesapeake Urologic Research Associates,
Baltimore, MD; Georgia Cancer Specialists PC, Atlanta, GA; Oncology Associates of San Diego, San Diego,
CA; Nebraska Cancer Specialists, Omaha, NE; University of Wisconsin Carbone Cancer Center, Madison,
WI; Aragon Pharmaceuticals, San Diego, CA
Abstract:
Background: ARN-509 is a novel small molecule androgen signaling inhibitor that impairs AR nuclear
translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist
activity. Preclinical data suggests that the maximal therapeutic index of ARN-509 can be achieved at low
steady state plasma levels with minimal toxicity (Clegg et al, 2012). Enrollment in the Phase 1 dose
escalation study of ARN-509 in patients with progressive CRPC with and without prior chemotherapy was
completed in January 2012. The recommended Phase 2 dose of 240 mg was determined based on safety,
PSA kinetics, and pharmacokinetic and pharmacodynamic analysis (Rathkopf et al, GU ASCO, 2012).
Methods: The primary objective of this Phase 2 study is to determine the PSA response at 12 weeks
according to Prostate Cancer Working Group 2 (PCWG2) Criteria (Scher et al, 2008). Three expansion
cohorts will enroll a total of 80-90 patients for treatment with 240 mg continuous oral ARN-509 daily. These
cohorts include: 1) non-metastatic treatment-naïve CRPC (50 patients); 2) chemotherapy-naïve metastatic
(m) CRPC (20 patients); and 3) chemotherapy-naïve, post abiraterone mCRPC (10-20 patients). The effect
of food on the PK of ARN-509 and the effect of ARN-509 on ventricular repolarization will also be evaluated.
Phase 2 enrollment is ongoing. DOD/PCF PCCTC trial sponsored by Aragon Pharmaceuticals.
NCT01171898.
Phase I clinical trial of galeterone (TOK-001), a multifunctional antiandrogen and CYP17 inhibitor in
castration resistant prostate cancer (CRPC).
Abstract No:4665
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4665)
Author(s): Robert B. Montgomery, Mario A. Eisenberger, Matthew Rettig, Franklin Chu, Roberto Pili, Joe
Stephenson, Nicholas J. Vogelzang, Jodie Morrison, Mary-Ellen Taplin; University of Washington, Seattle,
WA; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, James Buchanan Brady
Urological Institute, Baltimore, MD; UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA; San
Bernadino Urological Associates, San Bernadino, CA; Roswell Park Cancer Institute, Buffalo, NY; Cancer
Centers of the Carolinas, Greenville, SC; Comprehensive Cancer Centers of Nevada and US Oncology
Research, Las Vegas, NV; Tokai Pharmaceuticals, Boston, MA; Dana-Farber Cancer Institute, Boston, MA
Abstract:
Background: Galeterone is an oral steroid analog that suppresses prostate cancer growth by inhibiting
CYP17, blocking androgen receptor and reducing androgen receptor levels. Methods: Open label,
multicenter dose-finding study assessing the safety, pharmacokinetics and clinical effect of escalating doses
of galeterone in chemotherapy naïve CRPC patients (pts). Pts were enrolled in cohorts from 650-2,600mg of
galeterone daily for 12 wks. Study also explored effects of food supplement and scheduling. Pts remained on
study until disease progression or dose limiting toxicity. Results: Pt characteristics included median age 69
(47-92), median PSA 24 (6-200), and 46.9% with metastases. 36 of 49 pts completed 12 wks of study with
early discontinuation for toxicity (6), progression (5), or withdrawal of consent (2). Maximal tolerated dose
was not reached. The frequency of AEs was 58% grade 1, 30% grade 2, 8% grade 3 and 1% grade 4.
Transient LFT elevations were seen in 15 men (5 with suspected or confirmed Gilberts). There was no trend
for increasing toxicity with dose escalation and no PK difference in Gilberts pts. 9 SAEs were reported with
one considered related to galeterone (rhabdomyolysis with acute renal failure in the context of high dose
statin use). Overall 11/49 pts (22%) demonstrated >50% PSA decline and an additional 13/49 (26%) had 3050% declines. Partial response by RECIST was seen in 2 pts. Consistent with lyase inhibition, increased
corticosteroids and suppressed androgens were seen with dose escalation. Analysis of limited plasma
collected 4 - 30 hours after dosing showed high interpatient variability with no consistent relationship to dose
or time after dosing. Conclusions: Galeterone was well tolerated in CRPC pts and demonstrated clinical
activity. Galeterone is being reformulated with additional PK and phase II trials planned.
PSA response to galeterone.
Dose (mg/day)
N
650
975 with and w/out supplement
1,300
1,950 single/split
2,600 single/split
*One pt nonevaluable.
6*
12*
6
13
12
Duration on
treatment
(months)
2-16
1-21
2-21
1-12
1-8
>50% PSA >30% PSA
decline
decline
% (n)
% (n)
20% (1)
20% (1)
18% (2)
55% (6)
0% (0)
17% (1)
23% (3)
54% (7)
42% (5)
75% (9)
VT-464: A novel, selective inhibitor of P450c17(CYP17)-17,20 lyase for castration-refractory prostate
cancer (CRPC).
Abstract No:e15167
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15167)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Joel Robert Eisner, David H Abbott, Ian M Bird, Stephen W Rafferty, William R Moore, Robert J
Schotzinger; Viamet Pharmaceuticals, Inc., Morrisville, NC; Wisconsin National Primate Research Center
and Department of Obstetrics and Gynecology, University of Wisconsin, Madison, WI; Perinatal Research
Laboratories and Department of Obstetrics and Gynecology, University of Wisconsin, Madison, WI
Abstract:
Background: CYP17 is a single protein with two distinct enzyme activities, 17 α-hydroxylase (hydroxylase)
and 17,20-lyase (lyase). Reduction of extra-gonadal androgen production through CYP17 inhibition is a
validated CRPC treatment paradigm. While treatment with the recently-approved CYP17 inhibitor,
abiraterone acetate (AA), increases overall survival in post-docetaxel CRPC patients (de Bono et al, N Engl
J Med 2011; 364:1995-2005), it is also associated with cortisol (F) suppression and increased steroid
concentrations up-stream of CYP17 hydroxylase. The clinical candidate VT-464 is an oral, non-steroidal,
lyase-selective CYP17 inhibitor. The study objectives were to compare VT-464 to abiraterone in regards to in
vitro selectivity and to compare VT-464 to AA in regards to in vivo primate endocrine response. Methods:
Human CYP17 hydroxylase and lyase IC50 values were determined for VT-464 and abiraterone in vitro.
Plasma progesterone (P), F, and testosterone (T) responses were measured 0-24 hours after single
subcutaneous doses of AA (12.5 mg/kg), VT-464 (6.25 and 12.5 mg/kg), or vehicle in adult, castrate, male
rhesus monkeys. Results: Human lyase and hydroxylase IC50 values were 69nM and 670nM for VT-464 and
15nM and 2.5nM for abiraterone, respectively. AA and both dose levels of VT-464 produced a similar overall
reduction in plasma T, compared to vehicle (p ≤ 0.009). AA treatment resulted in an elevated plasma P (peak
increase >9,000%; p ≤ 0.05), compared to both VT-464 treatments and vehicle. F was not affected by either
VT-464 dose, whereas AA resulted in F suppression (p ≤ 0.005) compared to vehicle. Conclusions: VT-464
was 10-fold more selective for human CYP17 lyase vs. hydroxylase inhibition. This selectivity was
associated with androgen suppression, but not increases of up-stream steroids or F suppression in male
monkeys. In contrast, abiraterone was 6-fold more selective for hydroxylase vs. lyase inhibition resulting in
associations with increased up-stream steroids and F suppression in AA-treated male monkeys, consistent
with clinical observations in CRPC. VT-464 may thus provide a more lyase-selective alternative to AA for
extra-gonadal androgen suppression in CRPC.
Temsirolimus (TEM) maintenance therapy after response of castration-resistant prostate cancer
(CRPC) to docetaxel (TAX).
Abstract No:e15177^
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15177^)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Urban Emmenegger, Christopher M. Booth, Scott R. Berry, Srikala S. Sridhar, Eric Winquist,
Nesan Bandali, Annabelle Chow, Christina R. Lee, Ping Xu, Shan Man, Robert S. Kerbel, Yoo-Joung Ko;
Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada; Queen's University Cancer
Research Institute, Kingston, ON, Canada; Princess Margaret Hospital, Toronto, ON, Canada; London
Health Sciences Centre, London, ON, Canada; Sunnybrook Research Institute, Toronto, ON, Canada
Abstract:
Background: There are no standard treatments for men who have demonstrated a good response to TAX
without signs of progression. The mTOR pathway is involved in many aspects of CRPC, and mTOR
inhibitors have shown significant anti-CRPC activity in preclinical testing. Therefore, we designed a phase II
trial to explore whether maintenance therapy with TEM has the potential to prolong response to TAX without
compromising quality of life. Methods: For this single-arm, multicenter phase II trial we recruited CRPC pts
with documented treatment response by PSA (> 50% decline from baseline) or RECIST (1.0) criteria
following ≥ 6 to 10 cycles of TAX (75 mg/m 2 q3wks). Subjects received weekly TEM (25 mg iv x 4/cycle). The
primary endpoint was time to treatment failure (TTF; RECIST or symptomatic progression). Secondary
endpoints included safety (NCI-CTCAE v3.0), quality of life (FACT-P, PPI), changes in PSA, objective tumor
response rate, and overall survival. We were also studying surrogate markers of TEM activity, including the
enumeration of circulating endothelial cells (CEC) as a potential indicator of the antiangiogenic effects of
TEM. Results: 19 pts have been enrolled to data after a median of 7 cycles of TAX. The mean age was 68
years (range 51-82), and the median baseline PSA 17.3 (0.02-380.7). 15 pts had received prior local
radiation therapy, 6 surgery. 17 pts had bone metastases, 9 visceral and 8 nodal disease. Pts received a
median of 4 cycles of TEM (maximum 23 and continuing), resulting in a median TTF of 5.8 (95%CI 3.8-9.2)
months. No PSA responses were seen (time to PSA progression 1.8 months), but 1 PR. 8 pts achieved SD.
12 pts have been discontinued due to treatment failure (RECIST [4], symptomatic [7], combined [1]), and 3
for other reasons, including TEM-associated toxicity (lymphedema [1]). TEM has been generally well
tolerated without unexpected adverse events or negative impact on quality of life. The median overall
survival has not yet been reached. There is a trend for TEM to reduce viable CEC amid large
inter/intrapatient CEC variability. Conclusions: TEM maintenance therapy in CRPC pts that have responded
to TAX appears to be well tolerated and results in meaningful prolonged TTF.
A phase I trial of AEZS-108 in castration- and taxane-resistant prostate cancer.
Abstract No:e15153
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15153)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Stephen V. Liu, Andrew V Schally, Tanya B. Dorff, Denice Tsao-Wei, Susan G. Groshen, Debra
Hawes, Shigang Xiong, David I. Quinn, Yu-Chong Tai, Norman L. Block, Juergen Engel, Jacek K. Pinski;
University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Veterans Affairs
Medical Center, University of Miami Miller School of Medicine, Miami, FL; California Institute of Technology,
Pasadena, CA; Aeterna Zentaris, Frankfurt, Germany
Abstract:
Background: The prognosis for patients with castration-resistant prostate cancer (CRPC) remains
suboptimal and targeted therapies should be explored. One potential target is the receptor for luteinizing
hormone-releasing hormone (LHRH), which is highly expressed on prostate cancer cells. AEZS-108 is an
LHRH-cytotoxic hybrid whose rational design covalently couples an LHRH agonist and the cytotoxic
doxorubicin. AEZS-108 exploits the presence of LHRH receptors to target delivery of the cytotoxic. We report
the phase I trial of AEZS-108 in men with taxane-resistant CRPC. We also report correlative studies of a
novel circulating tumor cell (CTC) capture device that will provide enumeration of CTCs and results from
AEZS-108 internalization studies that exploit the auto-fluorescence of doxorubicin in captured CTCs.
Methods: This is a single-arm, dose-escalation phase I study in men with CRPC to confirm the dose
established in a completed phase I trial in females. Eligibility criteria included adequate organ function and
progression of disease despite prior therapy with an LHRH agonist and at least one taxane-based regimen.
Patients were required to discontinue LHRH agonists to avoid receptor competition. Due to potential
cardiotoxicity, patients with an ejection fraction < 50% or prior exposure to doxorubicin or mitoxantrone were
excluded. Pituitary function was closely monitored. Patients received AEZS-108 every 21 days for up to 6
cycles until progression or unacceptable toxicity. The primary endpoint was safety. Results: Enrollment
began in November 2010 and is ongoing. Currently, 13 patients have been enrolled. The first two planned
dose levels had no dose-limiting toxicities observed. Two patients on the third dose level experienced a dose
limiting toxicity. The second dose level has been reopened for expansion. There have been no cardiac or
pituitary toxicities. At the time of submission, a decrease in PSA was noted in 6 of the 13 patients. Final
results detailing safety, response and the suggested dose for the phase II portion will be reported. All
correlative studies will also be reported. Conclusions: In general, AEZS-108 has been well tolerated. The
phase II portion of the study will begin once the MTD is established.
A phase II study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with
bone-metastatic castration-resistant prostate cancer (CRPC): A PCCTC trial.
Abstract No:4654
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4654)
Author(s): Emmanuel S. Antonarakis, Elisabeth I. Heath, Edwin M. Posadas, Michael Roger Harrison,
Justine Yang Bruce, Evan Y. Yu, Steve Y. Cho, Gregory E. Wilding, Gerald J. Fetterly, David G. Hangauer,
Min-Fun Rudolf Kwan, Lyn M. Dyster, Michael Anthony Carducci, Prostate Cancer Clinical Trials Consortium
(PCCTC); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD;
Karmanos Cancer Institute, Wayne State University, Detroit, MI; Samuel Oschin Comprehensive Cancer
Institute, Cedars-Sinai Medical Center, Los Angeles, CA; Duke Cancer Institute, Durham, NC; University of
Wisconsin Carbone Cancer Center, Madison, WI; Fred Hutchinson Cancer Research Center, Seattle, WA;
State University of New York at Buffalo, Buffalo, NY; Roswell Park Cancer Institute, Buffalo, NY; Kinex
Pharmaceuticals LLC, Buffalo, NY
Abstract:
Background: KX2-391 is an oral small molecule inhibitor of Src kinase and tubulin polymerization. In phase
1 trials, PSA declines were seen in men with advanced prostate cancer. Methods: A single-arm phase 2
study of KX2-391 in 31 men with chemo-naïve bone-metastatic CRPC was conducted at 5 PCCTC sites.
Men received oral KX2-391 (40 mg BID) until disease progression or unacceptable toxicity. The primary
endpoint was progression-free survival (PFS) at 24 wk (progression = clinical/radiographic progression or
death, but not rising PSA; PCWG2 criteria); a 50% success rate was predefined as clinically significant.
Secondary endpoints were PSA progression-free survival (PPFS) at 24 wk (PSA progression = 25% PSA
rise above nadir; PCWG2 criteria); median PFS; median PPFS; and max PSA decline. Exploratory outcomes
included PK studies, CTC enumeration, and analysis of markers of bone resorption (urinary N-telopeptide
[uNTx]; C-telopeptide [CTx]) and formation (bone alk phos [BAP]; osteocalcin). Results: The trial closed
early after accrual of 31 men, due to a prespecified futility rule. In all, 26/31 men were evaluable for the
primary endpoint; efficacy results are shown below. Also, 2/11 men (18%) with unfavorable (≥5) CTCs at
baseline converted to favorable (<5) CTC counts on study, and 18/19 men (95%) with baseline favorable
CTC counts maintained them. The proportion of men with declines in bone turnover markers was 32% (8/25)
for uNTx, 21% (6/29) for CTx, 10% (3/29) for BAP, and 25% (7/28) for osteocalcin. In PK studies, median
Cmax was 61 (range 16–129) ng/mL, and AUC was 156 (35–348) ng*hr/mL. Common toxicities (≥10%)
included LFT elevations, leukopenia, thrombocytopenia, fatigue, nausea and constipation. Conclusions:
KX2-391 dosed at 40 mg BID lacks antitumor activity in men with CRPC, but modulates bone turnover
markers in some men. Because a Cmax of >142 ng/mL is required for tubulin polymerization inhibition, higher
once-daily dosing will be used in future trials.
Endpoint
Value 95% CI
Primary
PFS at 24 wk (%)
7.7
2.3 – 24.3
Secondary
PPFS at 24 wk (%)
0
0 – 13.2
Median PFS (wk)
18.6 12.1 – 24.0
Median PPFS (wk)
5.0
4.1 – 11.4
≥30% PSA decline (%) 9.7
3.5 – 25.0
Phase I results from a phase I/II study of orteronel, an oral, investigational, nonsteroidal 17,20-lyase
inhibitor, with docetaxel and prednisone (DP) in metastatic castration-resistant prostate cancer
(mCRPC).
Abstract No:4656
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4656)
Author(s): Daniel Peter Petrylak, Jitendra G. Gandhi, William R. Clark, Elisabeth I. Heath, Jianqing Lin,
William K. Oh, David B. Agus, Omer Kucuk, Susan Moran, Jingyuan Wang, Michael Bargfrede, Glenn Liu;
Columbia University Medical Center, New York, NY; Associates in Oncology and Hematology, Chattanooga,
TN; Alaska Clinical Research Center, Anchorage, AK; Karmanos Cancer Institute, Detroit, MI; Thomas
Jefferson University Hospital, Philadelphia, PA; Mount Sinai Hospital, New York, NY; University of Southern
California Keck School of Medicine, Beverly Hills, CA; Winship Cancer Institute, Emory University, Atlanta,
GA; Millennium Pharmaceuticals, Cambridge, MA; University of Wisconsin Carbone Cancer Center,
Madison, WI
Abstract:
Background: The investigational agent orteronel (ortl, TAK-700) is a selective 17,20-lyase inhibitor that
blocks androgen production. Since DP is standard chemotherapy in mCRPC, this phase 1/2 study examined
ortl + DP in men with mCRPC. Methods: The primary phase I objective was to determine the maximum
dose of ortl 200–400 mg BID that can be administered safely with DP in castrate men (testosterone [T] <50
ng/dL) with mCRPC, ≤1 prior chemotherapy and no ketoconazole/abiraterone ≤30 d prior. A 3+3 dose
escalation was used with ortl 200 then 400 mg BID. Ortl dosed daily and D (75 mg/m 2 q3w) + P (5 mg BID)
was started on d8 of cycle 1 (28 d); cycles ≥2 = 21 d. Results: 14 men, median age 68 yrs (range 53–81),
ECOG PS 0/1 (71%/29%), median PSA 59.4 ng/mL (5.2–1052), T 8.1 ng/dL (1.2–16.7), 9 with measurable
disease, were treated. Median ortl exposure was 33.3 wks (6.3–59); 6 and 8 men received ortl 200 and 400
mg BID + DP, in cohorts 1 and 2, respectively. No dose-limiting toxicities (DLTs) occurred in cohort 1 (2 x 3
pts); in cohort 2 (2 x 4 pts), 1 pt in group 1 had DLT (Gr3 related febrile neutropenia); no DLTs occurred in
group 2. 3 pts discontinued due to AEs (2 D infusion reactions, 1 at each dose; 1 unrelated cardiorespiratory
death at 200 mg). All men had at least 1 AE Gr ≥3 which were treatment-related in 11 men. The most
common Gr ≥3 AEs were seen at both doses and included neutropenia 50% (n = 7), hyperglycemia 21% (n =
3), febrile neutropenia, infusion reaction, hyponatremia, decreased neutrophil count (2 each); at 400 mg only:
fatigue, hypophosphatemia, and decreased WBC count (2 each). 7 men had serious AEs (SAEs), which
were drug-related in 5. The most common SAE was febrile neutropenia in 2 men. At 3 mo, PSA50 and
PSA90 rates were 86% and 36%, respectively; 12/14 men had a median PSA decline ≥70%; and median T
declined to ≤0.2 ng/dL (0–10.7). The Cmax of D + ortl was similar to D alone. Conclusions: Ortl 200 mg and
400 mg BID + DP appears safe and tolerable with androgen-lowering activity at the maximum planned dose
in mCRPC. There is no evidence of AE potentiation when ortl is administered with DP. The phase II portion
of the study will use ortl 400 mg BID + DP.
Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in
metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane.
Abstract No:4662
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4662)
Author(s): Anthony E. Mega, Daniel Peter Petrylak, Philip Kantoff, Joe Stephenson, Nicholas J. Vogelzang,
Robert Dreicer, Neal D. Shore, Nancy Stambler, Jennifer Carpenito, Paul D'Ambrosio, Robert Joseph Israel;
Brown University Oncology Group, Providence, RI; Columbia University Medical Center, New York, NY;
Dana-Farber Cancer Institute, Boston, MA; Cancer Centers of the Carolinas, Greenville, SC; Comprehensive
Cancer Centers of Nevada and US Oncology Research, Las Vegas, NV; Cleveland Clinic, Cleveland, OH;
Carolina Urologic Research Center, Myrtle Beach, SC; Progenics Pharmaceuticals, Inc., Tarrytown, NY
Abstract:
Background: The abundant expression of prostate specific membrane antigen (PSMA) type II
transmembrane glycoprotein on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC,
a fully humanized antibody to PSMA linked to the potent antitubulin agent monomethyl auristatin E (MMAE),
binds PSMA and is internalized within the prostate cancer cell where cleavage by lysosomal enzymes and
releases free MMAE, causing cell cycle arrest and apoptosis. We report results from an ongoing phase 1
dose escalation study of PSMA ADC in subjects with taxane-refractory mCRPC. Methods: Eligibility
requirements include progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0
or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Adverse events, pharmacokinetics
(PK), PSA, circulating tumor cells, clinical disease progression and immunogenic response to PSMA ADC
were assessed. Serum PSMA ADC and total antibody were measured by ELISA, and free MMAE was
measured by LC/MS/MS.The dosing cohorts range from 0.4 mg/kg to 2.8 mg/kg, with dose escalation
continuing. Results: 40 subjects have been dosed in nine dose levels (0.4, 0.7, 1.1, 1.6, 1.8, 2.0, 2.2, 2.5,
2.8 mg/kg). To date, PSMA ADC has been well tolerated with the most commonly seen adverse events
being anorexia and nausea, and the most common laboratory abnormalities being reversible hematologic
parameters and liver function tests. Antitumor activity has been manifested as reductions either in PSA or
circulating tumor cells in the higher dose cohorts. Exposure to PSMA ADC increased with dose and was
~1,000-fold greater than MMAE exposure. Similar PK metrics were observed after the first and third doses.
Dosing at the 2.8 mg/kg cohort is continuing and an MTD has not yet been reached. Conclusions: PSMA
ADC is generally well tolerated in subjects with mCRPC, previously treated with taxane in doses up to 2.8
mg/kg. Antitumor activity at higher dose levels has been observed. The MTD has not yet been reached and
enrollment is ongoing at higher dose levels.
CA184-095: A randomized, double-blind, phase III trial to compare the efficacy of ipilimumab versus
placebo in asymptomatic or minimally symptomatic patients (pts) with metastatic chemotherapynaive castration-resistant prostate cancer (CRPC).
Abstract No:TPS4691
Citation:
J Clin Oncol 30, 2012 (suppl; abstr TPS4691)
Author(s): Tomasz M. Beer, Christopher Logothetis, Padmanee Sharma, Alberto Bossi, Brent McHenry,
Justin P. Fairchild, Paul Gagnier, Kevin M. Chin, Jean-Marie Cuillerot, Karim Fizazi, Winald R. Gerritsen;
Oregon Health & Science University Knight Cancer Institute, Portland, OR; University of Texas M. D.
Anderson Cancer Center, Houston, TX; Institut Gustave Roussy, Villejuif, France; Bristol-Myers Squibb,
Wallingford, CT; VU University Medical Center, Amsterdam, Netherlands
Abstract:
Background: Ipilimumab (Ipi), a fully human monoclonal antibody which blocks CTLA-4, augments
antitumor immune responses. Ipi has demonstrated overall survival (OS) benefit in two Phase 3 trials for
advanced melanoma, with side effects that were managed using product-specific treatment guidelines. In
addition, in Phase 1/2 trials in metastatic CRPC, Ipi has shown clinical activity (as measured by prostatespecific antigen [PSA] declines and RECIST response) with no unexpected toxicities. While docetaxel is
standard therapy for metastatic CRPC, its use may be delayed until pts develop symptoms. As such, this
global (~150 sites in 25 countries) Phase 3 study (ClinicalTrials.gov identifier: NCT01057810) is evaluating
Ipi vs placebo in chemotherapy-naïve pts with asymptomatic or minimally symptomatic CRPC without
visceral metastases. Methods: The primary endpoint is OS; secondary endpoints include progression-free
survival, time to pain progression, and time to non-hormonal systemic therapy. The study is designed to
detect a 9.3 month difference (HR=0.7) in OS with 90% power and 0.05 two-sided significance. Pts are
randomized at a 2:1 ratio to receive Ipi 10 mg/kg every 3 weeks for up to 4 doses or placebo, respectively,
as induction therapy. Eligible pts will continue to receive maintenance therapy of blinded study drug every 12
weeks until treatment stopping criteria are met, withdrawal of consent, or study closure. The accrual goal is
600 pts randomized.
Inclusion criteria
Metastatic CRPC
Asymptomatic or minimally symptomatic
Progression during prior hormonal therapy
Discontinuation of anti-androgens
Testosterone < 50 ng/dl
ECOG Performance Status 0-1
Exclusion criteria
Liver, lung, or brain metastases
Prior immunotherapy or chemotherapy for metastatic CRPC
Autoimmune disease
HIV, Hep B, or Hep C infection
Pelvic targeted radiotherapy within 3 months of study
A phase III, randomized, double-blind, multicenter trial comparing the investigational agent orteronel
(TAK-700) plus prednisone (P) with placebo plus P in patients with metastatic castration-resistant
prostate cancer (mCRPC) that has progressed during or following docetaxel-based therapy.
Abstract No:TPS4693
Citation:
J Clin Oncol 30, 2012 (suppl; abstr TPS4693)
Author(s): Robert Dreicer, David B. Agus, Joaquim Bellmunt, Johann Sebastian De Bono, Daniel Peter
Petrylak, Bindu Tejura, Yuanjun Shi, Karim Fizazi; Cleveland Clinic, Cleveland, OH; University of Southern
California Keck School of Medicine, Beverly Hills, CA; University Hospital del Mar, Barcelona, Spain; The
Institute for Cancer Research, London, United Kingdom; Columbia University Medical Center, New York, NY;
Millennium Pharmaceuticals, Cambridge, MA; Institut Gustave Roussy, Villejuif, France
Abstract:
Background: The investigational agent orteronel is a selective inhibitor of 17,20-lyase, a key enzyme in the
testosterone synthesis pathway. In a phase 1/2 study in men with mCRPC, orteronel reduced prostatespecific antigen (PSA) levels, and inhibited testosterone and DHEA-S consistent with potent 17,20-lyase
inhibition (Agus D, et al. J Clin Oncol 2012;30:s5 abst 98). Docetaxel-based chemotherapy is an effective but
noncurative therapy for mCRPC that has progressed on hormonal therapy; new therapeutic options are
needed. Methods: This double-blind, multicenter study is assessing orteronel + P vs placebo + P in men
with mCRPC (NCT01193257; C21005). Patients must have evidence of disease progression during or after
receiving a total of ≥360 mg/m 2 docetaxel within a 6-mo period. Patients who are clearly intolerant to
docetaxel or have progressive disease before receiving ≥360 mg/m 2 are also eligible if they have received at
least 225 mg/m2 of docetaxel within a 6-mo period and meet the other inclusion criteria. Other eligibility
criteria include radiographically documented metastatic disease and baseline testosterone <50 ng/dL
following surgical or medical castration. Prior adrenal-targeted therapies are not permitted. Men may have
opioid-requiring bone pain. The planned sample size is 1083; men will be randomized 2:1 to receive
orteronel 400 mg twice daily (BID) plus P 5 mg BID or placebo plus P. The primary endpoint is overall
survival; other endpoints are radiographic progression-free survival, PSA decrease of ≥50% at 12 wks, pain
response at 12 wks, safety, time to PSA progression, objective response by RECIST, circulating tumor cell
and endocrine marker changes, and patient-reported outcomes. After disease progression, men may
continue to receive study drug. Tumor specimens will be analyzed for biomarkers that may predict orteronel
antitumor activity, including the TMPRSS2:ERG fusion gene. The same regimens are being evaluated in a
concurrent phase 3 study in chemotherapy-naïve men with mCRPC (NCT01193244).
A randomized phase II study of OGX-427 plus prednisone (P) versus P alone in patients (pts) with
metastatic castration resistant prostate cancer (CRPC).
Abstract No:4514
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4514)
Author(s): Kim N. Chi, Sebastien J. Hotte, Susan Ellard, Joel Roger Gingerich, Anthony Michael Joshua,
Evan Y. Yu, Martin Edwin Gleave; British Columbia Cancer Agency, Vancouver, BC, Canada; Juravinski
Cancer Centre, Hamilton, ON, Canada; Cancer Centre for Southern Interior, Kelowna, BC, Canada;
University of Manitoba, Winnipeg, MB, Canada; Princess Margaret Hospital, Toronto, ON, Canada; Fred
Hutchinson Cancer Research Center, Seattle, WA; Vancouver Prostate Centre, Vancouver, BC, Canada
Abstract:
Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone protein that regulates cell
signaling and survival pathways implicated in cancer progression. In prostate cancer models, Hsp27
complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes. OGX-427 is a
2nd generation antisense oligonucleotide that inhibits Hsp27 expression with in vitro and in vivo efficacy and
was well tolerated with single agent activity in phase I studies. Methods: Chemotherapy-naïve pts with
no/minimal symptoms were randomized to receive OGX-427 600 mg IV x 3 loading doses then 1000 mg IV
weekly with P 5 mg PO BID or P only. Primary endpoint was the proportion of pts progression free (PPF) at
12 weeks (PCWG2 criteria). A 2-stage MinMax design (H0 = 5%, HA >20%, α=0.1, β=0.1) with 32 pts/arm
provides 70% power to detect the difference at 0.10 1-sided significance. Secondary endpoints include PSA
decline, measurable disease response, and circulating tumour cell (CTC) enumeration. Results: 38 pts have
been enrolled; 1st stage of accrual completed with 2nd stage accruing. In the 1st 32 pts randomized (17 to
OGX-427+P, 15 to P), baseline median age was 71 years (53-89), ECOG PS 0 or 1 in 66% and 34% of pts,
median PSA 66 (6-606), metastases in bone/lymph nodes/liver or lung was 75/56/9%, 31% had prior P
treatment, and 93% had ≥5 CTC/7.5 ml. Predominantly grade 1/2 infusion reactions (chills, diarrhea,
flushing, nausea, vomiting) occurred in 47% of pts receiving OGX-427+P. One pt on OGX-427+P developed
hemolytic uremic syndrome. A PSA decline of ≥50% occurred in 41% of pts on OGX-427+P, and 20% of pts
treated with P. A measurable disease partial response was seen in 3/8 (38%) evaluable pts on OGX-427+P
and 0/9 pts on P. CTC conversion from ≥5 to <5/7.5 ml occurred in 50% of pts on OGX-427+P and 31%
treated with P. Thus far, in 26 evaluable pts the PPF at 12 weeks was 71% (95% CI: 42-92) in OGX-427+P
treated pts and 33% (95% CI: 10-65) in pts on P. Conclusions: These data provide clinical evidence for the
role of Hsp27 as a therapeutic target in prostate cancer and support continued evaluation of OGX-427 for pts
with CRPC. Funded by a grant from the Terry Fox Research Institute.
Survival in metastatic castration resistant prostate cancer (mCRPC) trial participants.
Abstract No:e15136
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15136)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Carmel Jo Pezaro, Aurelius Gabriel Omlin, Deborah Mukherji, Diletta Bianchini, Shahneen Kaur
Sandhu, Amy Mulick Cassidy, Gal Maier, David Olmos, Emilda Thompson, Gerhardt Attard, Johann
Sebastian De Bono; The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton,
United Kingdom; The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton,
United Kingdom; The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton,
United Kingdom
Abstract:
Background: Median overall survival (mOS) in patients (pts) with metastatic prostate cancer progressing
despite castrate levels of testosterone (mCRPC) was 13-16 months (m) in the pre-docetaxel era. These
data, obtained from clinical trials, were used to construct currently available prognostic nomograms. We
hypothesise that these models no longer reflect survival. Pts and physicians urgently require updated
prognostic data on which to base management decisions. Methods: Pts with mCRPC treated on phase I-III
trials at our institution were identified and data retrospectively collected. Predicted survival by Halabi and
Smaletz nomograms were compared to calculated survival using Kaplan-Meier analysis. Cox model
multivariate (MV) analysis used variables at referral, including performance status (PS), Gleason (GS),
prostate specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), hemoglobin
(Hb), visceral disease and albumin. Results: 423 pts with CRPC treated between 2003 and 2011 were
included. At diagnosis median age was 62 years (y; 41.8 – 82.7); 226 (53.4%) had metastatic disease.
Median interval from diagnosis to CRPC was 2.7y (0.2 – 21.7). At referral 248 pts (58.6%) were
chemotherapy-naïve. Halabi and Smaletz models predicted mOS in chemo-naïve pts of 21m and 18m
respectively, however the observed mOS was 32m (95%CI 28 – 38). Survival from CRPC was 43m (CI 37 –
46) and 39m (CI 34 - 44) in pre- and post-chemo pts, respectively. Conclusions: Despite aggressive
disease characteristics, our pts lived significantly longer than predicted by current nomograms. MV analysis
confirmed the importance of several previously identified prognostic factors. Survival data from this large
cohort of CRPC pts should encourage men considering clinical trial participation. Previously developed
nomograms no longer accurately predict survival.
Testosterone levels as a prognostic factor for survival in patients with castrate-restistant prostate
cancer (CRPC).
Abstract No:e15159
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15159)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Alfonso Gomez de Liaño, José Pablo Maroto, Cristina Martin Lorente, Elena Cillan, Ismael
Macias, Agostina Stradella, Ivana Sullivan, Paola Murata, Cristina Arqueros, Georgia Anguera, Dhiossett
Condori, Agust Barnadas; Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Abstract:
Background: To analyze the prognostic value for survival of the absolute levels of serum testosterone in
patients under the definition of CRPC (PSA and/or clinical progression with a testosterone level below 50
ng/dL). Methods: 49 patients were included in 4 non-hormonal first line phase II-III trials in our institution
since August 2006 until Jan 2012 for metastatic CRPC. Inclusion criteria of those trials uniformly required
castrate levels of testosterone. Survival was calculated since the date of entrance in the trial. Results:
Median age was 71 years (53-89). 9/49 (18%) of the patients had visceral metastases. Median PSA was
66.7 U/L (0.1-936). Median testosterone level was 11.54 ng/dL (range 0.2-49.9). All patients had metastatic
prostate cancer, previous treatment consisted of at least 2 hormonal maneuvers (adding or stopping
antiandrogen for a wash-up period of 42 days for bicalutamide). All patients received at least one line of
chemotherapy for CRPC as part of the trial or after the completion of the trial. Median survival was 21.85
months. For 26 patients with a serum testosterone level below the median value, median survival was 17
months and 35.45 months for those patients with a testosterone level over 11.51 ng/dL (p value 0.036).
Conclusions: Testosterone serum levels even under castration level (below 50 ng/dL) were a prognostic
factor for survival in patients with metastatic prostate cancer considered castration resistant.
Pharmacoeconomics
Therapeutic options in metastatic castration-resistant prostate cancer (mCRPC): A costeffectiveness analysis.
Abstract No:e15154
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15154)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Lixian Zhong, Sandy Srinivas, Vickie Pon, Nicole Nguyen, Meghan Frear, Sherry Kwan, Cynthia
Gong, Robert Malmstrom, Aimee Loucks, Leslie Wilson; UCSF, San Francisco, CA; Stanford Medical
Center, Stanford, CA; VA Northern California Health Care system, Martinez, CA
Abstract Disclosures
Abstract:
Background: Initial therapy for metastatic prostate cancer is androgen deprivation therapy. Uniformly
progression of disease occurs despite castration. Docetaxel is then the standard of care. Abiraterone (Abi)
and cabazitaxel (Cab) are approved for mCRPC post docetaxel with improvements in survival We seek to
evaluate the cost-effectiveness of Abi and Cab compared to mitoxantrone (Mit) and prednisone for mCRPC.
Methods: A decision tree model was constructed comparing four treatments for mCRPC patients over an 18
month period: 1) Abi, 2) Cab, 3) Mit, and 4) prednisone only. Chance nodes included baseline pain as a
severity indicator, grade III & IV adverse events (AE) (neutropenia and cardiac ) and survival at 18mos.
Survival rates and probabilities were from published data. Cost of drug regimens were based on 2010 US
dollars and average wholesale price (AWP). Model cost inputs included drug-costs, administration costs,
management of AE’s, radiation for pain, and costs associated with death. Health utilities for baseline pain,
bone pain, neutropenia, cardiac events, and radiation were obtained from published data. Sensitivity
analyses were conducted focused on baseline severity and costs of drug. Results: Base case estimates
suggest that Cab and Abi are most effective. The incremental cost effectiveness ratio (ICER) for Mit vs.
placebo is $110K/QALY, Abi vs. Mit is $76K/QALY and for Cab vs. Abi, the ICER is $925K/QALY. Modelsensitive parameters include Abi AWP and cost of Mit side effect management; Abi becomes less costeffective as its AWP increases, or if the cost of Mit side effect management decreases. When baseline
severity increases, Mit becomes cost-effective over placebo and Abi remains cost-effective over Mit. Cab
remains not cost-effective at tolerable thresholds. Conclusions: Compared to Cab, Mit, and placebo, Abi is
the most cost-effective option in docetaxel-refractory mCRPC patients due to its ability to prolong survival
and maintain a willingness-to-pay threshold (WTP) of $100K. Despite higher survival with Cab, it is not costeffective because of costs associated with treatment of neutropenia. In situations where illness is more
severe, Abi remains the cost-effective choice.