INFORMACIÓN ESPECIAL
Noviembre 2015 VOL 5 (6)
Biblioteca INOR
Patients with metastatic castration-resistant prostate cancer
Annals of Oncology November 2015 Volume 26, Issue 11
Pp. 2221-2247
Assessment of anticancer-treatment outcome in patients with metastatic
castration-resistant prostate cancer—going beyond PSA and imaging, a
systematic literature review
S. Schmid1,†,*, A. Omlin1,†, D. Blum2, F. Strasser1,2, S. Gillessen1,‡ and C.
Rothermundt1,
Abstract
Background In the past years, there has been significant progress in anticancer drug
development for patients with metastatic castration-resistant prostate cancer (CRPC).
However, the current instruments to assess clinical treatment response have limitations and
may not sufficiently reflect patient benefit. Our objective was to systematically identify
tools to evaluate both patient benefit and clinical anticancer-treatment response as basis for
an international consensus process and development of a specific pragmatic instrument for
men with CRPC.
Methods PubMed, Embase and CINAHL were searched to identify currently available
tools to assess anticancer-treatment benefit, other than standard imaging procedures and
prostate-specific antigen measurements, namely quality of life (QoL), detailed pain
assessment, physical function and objective measures of other complex cancer-related
syndromes in patients with CRPC. Additionally, all CRPC phase III trials published in the
last 5 years were reviewed as well as studies using physical function tools in a general
cancer population. The PRIMSA statement was followed for the systematic review process.
Results The search generated 1096 hits, 185 full-text papers were screened and finally 73
publications were included. Additional 89 publications were included by hand-search. We
identified a total of 98 tools used in CRPC trials and grouped these into three categories: 22
tools assessing QoL domains and subgroups, 47 tools for pain assessment and 29 tools for
objective measures, mainly physical function and assessment of skeletal disease burden.
Conclusion A wide variety of assessment tools and also efforts to standardize and
harmonize patient-reported outcomes and pain assessment were identified. However, the
specific needs of the increasing CRPC population living longer with their incurable cancer
are insufficiently captured and objective physical outcome measures are under-represented.
In the age of new anticancer drug targets and principles, new methods to monitor patient
relevant outcomes of antineoplastic therapy are of utmost importance.
****
Br J Cancer. 2015 May 12;112(10):1717-24. doi: 10.1038/bjc.2015.128. Epub 2015 Apr 21.
Circulating cell-free AR and CYP17A1 copy number variations
may associate with outcome of metastatic castration-resistant
prostate cancer patients treated with abiraterone.
Salvi S1, Casadio V1, Conteduca V2, Burgio SL2, Menna C2, Bianchi E2, Rossi L2, Carretta E3, Masini C4,
Amadori D2, Calistri D1, Attard G5, De Giorgi U2.
Author information
Abstract
BACKGROUND:
This study aimed to investigate copy number variations (CNVs) of CYP17A1 and androgen
receptor (AR) genes in serum cell-free DNA collected before starting abiraterone in 53
consecutive patients with castration-resistant prostate cancer (CRPC).
METHODS:
Serum DNA was isolated and CNVs were analysed for AR and CYP17A1 genes using
Taqman copy number assays. The association between CNVs and progression-free/overall
survival (PFS/OS) was evaluated by the Kaplan-Meier method and log-rank test.
RESULTS:
Median PFS of patients with AR gene gain was 2.8 vs 9.5 months of non-gained cases (P <
0.0001). Patients with CYP17A1 gene gain had a median PFS of 2.8 months vs 9.2 months
in the non-gained patients (P = 0.0014). A lower OS was reported in both cases (AR: P <
0.0001; CYP17A1: P = 0.0085). Multivariate analysis revealed that PSA decline ⩾ 50%,
AR and CYP17A1 CNVs were associated with shorter PFS (P < 0.0001, P = 0.0004 and P
= 0.0450, respectively), while performance status, PSA decline ⩾ 50%, AR CNV and DNA
concentration were associated with OS (P = 0.0021, P = 0.0014, P = 0.0026 and P = 0.0129,
respectively).
CONCLUSIONS:
CNVs of AR and CYP17A1 genes would appear to be associated with outcome of CRPC
patients treated with abiraterone.
****
BMC Cancer. 2015 Apr 4;15:222. doi: 10.1186/s12885-015-1257-2.
Abiraterone acetate in patients with metastatic castration-resistant
prostate cancer: long term outcome of the Temporary Authorization for
Use programme in France
.
Houédé N1,2, Beuzeboc P3, Gourgou S4, Tosi D5, Moise L6, Gravis G7, Delva R8, Fléchon A9, Latorzeff
I10, Ferrero JM11, Oudard S12, Tartas S13, Laguerre B14, Topart D15, Roubaud G16, Agherbi H17,
Rebillard X18, Azria D19,20.
BACKGROUND:
COU-AA-301 trial has proved that abiraterone acetate (AA), a selective inhibitor of
androgen biosynthesis, improved overall survival (OS) of patients with metastatic
castration resistant prostate cancer (mCRPC) after a first line of docetaxel. Based on this
result, a Temporary Authorization for Use (TAU) was performed between December 2010
and July 2011 to provide patients with mCRPC the opportunity to receive AA before its
commercialization. The aim of this study was to evaluate safety and efficacy of AA
treatment in this TAU.
METHODS:
Between December 2010 and July 2011, we conducted an ambispective, multicentric
cohort study and investigated data from 20 centres participating to the AA TAU for patients
presenting mCRPC and already treated by a first line of chemotherapy (CT). Statistical
analyses of the data were performed using the Stata software v13 to identify predictive and
prognostic factors.
RESULTS:
Among the 408 patients, 306 were eligible with a follow-up at 3 years. Median OS was
37.1 months from beginning of CT and 14.6 months from AA introduction. 211 patients
(69%) received ≥ 3 months of AA and 95 patients (31%) were treated less than 3 months. In
the multivariate analyses, duration of AA was significantly correlated with PSA decrease at
3 months. Additionally, shorter time under AA treatment, presence of multiple sites of
metastasis and previous hormonal treatment duration were three independent factors
associated with poorer OS. At the time of analysis ten patients were still under treatment for
more than 3 years.
CONCLUSIONS:
Biochemical response monitored by PSA changes at 3 months is a strong predictive factor
for AA treatment duration. Some high responders' patients could beneficiate from AA for
more than 3 years.
Eur Urol. 2014 Nov;66(5):815-25. doi: 10.1016/j.eururo.2014.02.056. Epub 2014 Mar 6.
Updated interim efficacy analysis and long-term safety of
abiraterone acetate in metastatic castration-resistant prostate
cancer patients without prior chemotherapy (COU-AA-302).
Rathkopf DE1, Smith MR2, de Bono JS3, Logothetis CJ4, Shore ND5, de Souza P6, Fizazi K7, Mulders
PF8, Mainwaring P9, Hainsworth JD10, Beer TM11, North S12, Fradet Y13, Van Poppel H14, Carles J15,
Flaig TW16, Efstathiou E4, Yu EY17, Higano CS17, Taplin ME18, Griffin TW19, Todd MB20, Yu MK19, Park
YC20, Kheoh T19, Small EJ21, Scher HI22, Molina A23, Ryan CJ21, Saad F24.
Author information
Abstract
BACKGROUND:
Abiraterone acetate (an androgen biosynthesis inhibitor) plus prednisone is approved for
treating patients with metastatic castration-resistant prostate cancer (mCRPC). Study COUAA-302 evaluated abiraterone acetate plus prednisone versus prednisone alone in mildly
symptomatic or asymptomatic patients with progressive mCRPC without prior
chemotherapy.
OBJECTIVE:
Report the prespecified third interim analysis (IA) of efficacy and safety outcomes in study
COU-AA-302.
DESIGN, SETTING, AND PARTICIPANTS:
Study COU-AA-302, a double-blind placebo-controlled study, enrolled patients with
mCRPC from April 2009 to June 2010. A total of 1088 patients were stratified by Eastern
Cooperative Oncology Group performance status (0 vs 1).
INTERVENTION:
Patients were randomised 1:1 to abiraterone 1000mg plus prednisone 5mg twice daily by
mouth versus prednisone.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:
Co-primary end points were radiographic progression-free survival (rPFS) and overall
survival (OS). Median times to event outcomes were estimated using the Kaplan-Meier
method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the
Cox model, and treatment comparison used the log-rank test. The O'Brien-Fleming LanDeMets α-spending function was used for OS. Adverse events were summarised
descriptively.
RESULTS AND LIMITATIONS:
With a median follow-up duration of 27.1 mo, improvement in rPFS was statistically
significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; HR: 0.52
[95% CI, 0.45-0.61]; p<0.0001). Abiraterone improved OS (median: 35.3 vs 30.1 mo; HR:
0.79 [95% CI, 0.66-0.95]; p=0.0151) but did not reach the prespecified statistical efficacy
boundary (α-level: 0.0035). A post hoc multivariate analysis for OS using known
prognostic factors supported the primary results (HR: 0.74 [95% CI, 0.61-0.89]; p=0.0017),
and all clinically relevant secondary end points and patient-reported outcomes improved.
While the post hoc nature of the long-term safety analysis is a limitation, the safety profile
with longer treatment exposure was consistent with prior reports.
CONCLUSIONS:
The updated IA of study COU-AA-302 in patients with mCRPC without prior
chemotherapy confirms that abiraterone delays disease progression, pain, and functional
deterioration and has clinical benefit with a favourable safety profile, including in patients
treated for ≥24 mo.
TRIAL REGISTRATION:
Study COU-AA-302, ClinicalTrials.gov number, NCT00887198.
PATIENT SUMMARY:
The updated results of this ongoing study showed that disease progression was delayed in
patients with advanced prostate cancer who were treated with abiraterone acetate and
prednisone, and there was a continued trend in prolongation of life compared with patients
treated with prednisone alone. Treatment with abiraterone acetate and prednisone was well
tolerated by patients who were treated for >2 yr.
Prostate. 2014 Nov;74(15):1560-8. doi: 10.1002/pros.22874. Epub 2014 Aug 31.
Clinical activity of enzalutamide in Docetaxel-naïve and
Docetaxel-pretreated patients with metastatic castrationresistant prostate cancer.
Nadal R1, Zhang Z, Rahman H, Schweizer MT, Denmeade SR, Paller CJ, Carducci MA, Eisenberger
MA, Antonarakis ES.
Author information
Abstract
BACKGROUND:
Two randomized clinical trials have demonstrated a survival advantage with enzalutamide
over placebo in both docetaxel (D)-pretreated and D-naïve metastatic castration-resistant
prostate cancer (mCRPC) patients. Cross-resistance between androgen receptor-directed
therapies and taxanes has been suggested, possibly leading to lower efficacy of
enzalutamide in the post-D setting.
METHODS:
We aimed to examine the impact of prior D treatment on the clinical activity of
enzalutamide in patients with mCRPC. We retrospectively reviewed an institutional
database to identify men with mCRPC treated with standard-of-care enzalutamide. Patients
were classified as D-naïve or D-pretreated. The efficacy end points were prostate-specific
antigen (PSA) response rates (≥ 50% PSA decline), time to PSA progression (TTPP) and
clinical/radiographic progression-free survival (PFS) in response to enzalutamide.
Differences between groups (D-naïve and D-pretreated) were assessed by univariate and
multivariable analyses using logistic and Cox regression models.
RESULTS:
One-hundred-seven (107) consecutive patients were included: 60 were D-pretreated and 47
were D-naïve. PSA responses were 43.2% in D-naïve patients and 25.4% in D-pretreated
patients (P = 0.089). Median TTPP was 7.2 months (95% CI = 4.5 - 17.2) in the D-naïve
group versus 2.6 mo (95% CI = 1.9 - 3.5) in the D-pretreated group (P < 0.0001). Median
PFS was not reached for D-naïve men and was 3.3 mo (95% CI = 2.5 - 4.8) for D-pretreated
men (P < 0.0001). After adjusting for potential confounders including prior abiraterone use,
differences remained statistically significant for TTPP (HR = 2.32; 95% CI = 1.19 - 4.50;
P = 0.013) and marginally significant for PFS (HR = 1.90; 95% CI = 0.94 - 3.84; P = 0.073)
in multivariable analyses. Among patients who achieved a PSA response to enzalutamide
(n = 34), results suggested a trend towards shorter duration of response in D-pretreated
patients.
CONCLUSIONS:
The clinical activity of enzalutamide appears to be blunted in patients who have previously
received docetaxel chemotherapy. These results support the concept of cross-resistance
between these two agents.
******
Oncotarget. 2014 Dec 15;5(23):12448-58.
Early outcome prediction on 18F-fluorocholine PET/CT in
metastatic castration-resistant prostate cancer patients treated
with abiraterone.
De Giorgi U1, Caroli P2, Burgio SL1, Menna C1, Conteduca V1, Bianchi E1, Fabbri F3, Carretta E3,
Amadori D1, Paganelli G2, Matteucci F2.
OBJECTIVE:
We investigated the role of 18F-fluorocholine positron emission tomography/computed
tomography (FCH-PET/CT) in the early evaluation of abiraterone and outcome prediction
in patients with metastatic castration-resistant prostate cancer (CRPC).
PATIENT AND METHODS:
Forty-three patients with metastatic CRPC progressing after docetaxel received abiraterone
1,000 mg daily with prednisone 5 mg twice daily. Patients were evaluated monthly for
serological PSA response and safety. FCH-PET/CT was done at baseline and after 3 to 6
weeks. Univariate and multivariate Cox regression models addressed potential predictors of
progression-free survival (PFS) and overall survival (OS).
RESULTS:
Declines in PSA level of ≥50% were seen in 21 of 43 (49%) patients. Forty-two patients
were evaluable for FCH-PET/CT response. FCH-PET/CT bone flare was observed in 4 of
42 (10%) evaluable patients. In univariate analysis, PSA decline and FCH-PET/CT
response predicted PFS, while PSA decline and FCH-PET/CT (progression vs non
progression) predicted OS. In multivariate analysis, only FCH-PET/CT (progression vs
nonprogression) remained significant for PFS and OS (p = 0.022 and p = 0.027,
respectively).
CONCLUSION:
Early FCH-PET/CT can predict clinical outcome in CRPC beyond PSA response. These
data support further studies on FCH-PET/CT for abiraterone monitoring and outcome
prediction in patients with CRPC.