Ian Davis presentation

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2011 ASCO Genitourinary

Cancers Symposium

17-19 February 2011, Orlando http://2011.gucasym.org/ www.anzup.org.au

General

• Approximately 500 participants, seemed more

• Program:

• Day 1: Prostate

– General Session I: Emerging Trends in the Characterization and Treatment Decisions in

Newly Diagnosed Prostate Cancer

– General Session II: Prostate Cancer Therapy for Recurrent Disease

– General Session III: Translational Science Session: New Targets for Prostate Cancer

Therapy

• Day 2: urothelial, penile, urethral, testicular

– General Session IV: Urothelial Carcinomas: Cases in Perioperative Chemotherapy

– Keynote Lecture:

• Stem Cells and Tumorigenesis in Genitourinary Tumors. Carlos Cordon-Cardo, MD, PhD -

Columbia University Medical Center

– General Session V: Penile, Urethral, and Testicular Cancers

– General Session VI: Translational Science Session: Urothelial Carcinomas

• Day 3: Renal

– General Session VII: Renal Cancer

– General Session VIII: Translational Science Session: Renal Cancer^

• Interspersed poster and poster discussion sessions, ticketed sessions

• Special seminars: emphasis on prostate cancer

Luo J, Solimini NL, Elledge SJ: Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction. Cell 136:823-837, 2009

High points: prostate

• PSA and GS are now included in AJCC stage

• NCCN now has “very low” risk category

– T1a: GS<6 <3 cores +ve and <50% involved

• New pathology reporting standards (next slide)

• PSA doubling time after RP:

– <4 months: probably metastatic

– >12 months: more likely local recurrence

• In testing for micrometastatic disease:

– RT-PCR

– CTC cut point 5 / 7.5 mL

– CTC-chip

– Circulating exosomes

• Three new treatments approved in US in 2010 for CRPC:

– Cabazitaxel, sipuleucel-T, denosumab

– (Abiraterone approved April 2011)

De Margo (Johns Hopkins): pathology

• TRUS is insensitive

– ~20% of patients are upgraded at RP

– One biopsy core ~ 1/3000 weight of prostate

• New markers:

– 34βE12 and p63 = basal markers; absent in PC

– AMACR positive in PC

• New pathology reporting:

– Always report secondary pattern of higher grade if present even if minor component eg 5%

– Separate GS report by core

– On core biopsy: any Gleason 5 implies high grade, called 8-10

– At RP: report primary/secondary and comment on tertiary

– Ductal adeno: automatically called 4+4=8

– Cribriform pattern previously 3 now 4

Shipley (MGH): RTOG 9601

• Background and rationale: to determine if long term antiandrogen therapy with RT improves cancer control and OS

• Design:

– Phase III, double-blind, placebo-controlled

– Postoperative pT2-3, N0, positive margins, elevated PSA <4 postop, negative scans

– RT ( RT (64.8 Gy in 1.8 Gy fractions) ± bicalutamide 150 mg/d during and after RT x 24 months

Note: not current treatment regimen

– Stratification: margins; nadir PSA < 0.5; entry PSA < 1.5; neoadjuvant short term ADT

– Primary endpoint: OS

Demographics:

– 771 patients, median age 65

– Median 2.1 yr between RP and study entry

– Median time RT to positive PSA 1.2 year

PSA failure defined as 0.4 from undetectable, or increase 0.3 above entry PSA

Results:

– 1-3% gr 3 early GU toxicity, 6% late

– 0.3-1% early gr 3 GI toxicity, 2% late

– OS 91% vs 86%; too few events yet (primary endpoint) B vs plac

– Mets: 7.4 vs 12% (p<0.041)

– FFP at 7 years: 57 vs 40% (p<0.02)

– Benefit across all groups

– PSADT benefit except in >2yr group

– Gynecomastia led to withdrawal in 8%

Fleshner (Toronto): REDEEM

• Reduction by Dutasteride of Clinical Progression Events in Expectant

Management of Prostate Cancer

• Testing whether dutasteride controls growth of existing low risk, localised prostate cancer reduces need for aggressive therapy in men followed with active surveillance

• 302 men, aged 4882, PSA <11 ng/mL, and GS ≤6 PCa (≥10 cores, ≤3 cores positive, <50% of any core positive)

• Randomised to dutasteride 0.5 mg/d or placebo for 3 years

• Repeat 12-core biopsies at 18 and 36 months, or for-cause at other times during the study

• Primary endpoint TTP: time to therapy, or pathology with ≥4 cores positive, or ≥50% involved or any GS ≥4

• Results:

– HR 0.61 risk of progression

– No cancer found in 23% of placebo and 36% dutasteride at 36 months

– QoL: less anxiety and fear of recurrence in D group, perhaps due to information about PSA

– No effect on sexual function

– No evidence of increased Gleason score upgrading with dutasteride

• Note: D shrinks gland so more likely to find any residual cancer

• Note: FDA warning issued 9 June 2011

Androgen Resistance:

Overlapping mechanisms

LHRH

Novel

Antiandrogens

AR amplification

(30%)

AR mutations?

CRPC

Intratumoral androgen production/conversion

Finasteride/Dutasteride

Ketoconazole

Abiraterone

Antiandrogens

Other proposed (outlaw) pathways:

• Indirect (ligand-independent) activation of AR activated in absence of androgen

Via tyrosine kinases (epidermal growth factor receptor), cytokines (interleukins)

• Signal transduction pathways nuclear factorκB

Apoptotic pathways

Persistent serum androgens (eg, adrenals)

Ketoconazole

Abiraterone

Steroids

Antiandrogens

Modified from: Van Allen EM, Ryan CJ. Curr Opinion Urol . 19:315-321. Bonkoff H, Berges R. Prostate.

2010;70:100-112.

Multiple mechanisms of action: points of targeted intervention in AR pathways

2.

Abiraterone ketoconazole

1. 17-AAG

AR degraded

Androgen precursors

AR

HSP90

2.

Adrenal synthesis

Tumor synthesis

Abiraterone ketoconazole

Androgens

Cell surface ligand/receptor

5. TKI inhibitors, antibodies

3. 5

-reductase

DHT inhibitors

Ack1 SRC mut

AR

AR AR

4. MDV-3100

BMS641988

P

AR AR

P

5. Dasatinib

Amp

AR

Antiandrogens, progestins, glucocorticoids

4.

MDV-3100

BMS641988

P

AR AR

6. HDACi (SAHA, LBH589)

P

Transcription of TMPRSS-ETS, etc for growth and survival

From: Chen Y et al. Curr Opin Pharmacol.

2008;8:440-448.

Study 301 Phase 3:

Randomized, Double-Blind,

Placebo-Controlled Trial in Patients

With CRPC Who Have Failed

Docetaxel-Based Chemotherapy

Prior Chemotherapy

Prednisone Add-on Therapy

Clinicaltrials.gov identifier: NCT00638690.

COU-AA-301 study design

Phase 3, multinational, multicenter, randomized, double-blind, placebocontrolled study (147 sites in 13 countries; USA, Europe, Australia, Canada)

Primary end point:

– 25% improvement in overall survival (HR = 0.8)

Secondary end points:

– Proportion of patients achieving a PSA decline ≥ 50% according to PSAWG criteria; time to PSA progression according to PSAWG criteria; PFS based on imaging studies;

CTC counts and profiling with outcome

• Stratification according to:

– ECOG performance status (0-1 vs. 2)

– Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs. 4-10 [present])

– Prior chemotherapy (1 vs. 2)

– Type of progression (PSA only vs. radiographic progression with or without PSA progression)

Data presented from interim analysis

Clinicaltrials.gov identifier: NCT00638690

COU-AA-301: All Secondary End

Points Achieved Statistical Significance

TTPP (months)

AA

(n = 797)

10.2

Placebo

(n = 398)

6.6

3.6

HR

95% CI

0.58

(0.46, 0.73)

0.67

(0.59, 0.78)

P Value

< 0.0001

< 0.0001

rPFS (months) 5.6

PSA response rate

Total

Confirmed

38.0%

29.1%

10.1%

5.5%

< 0.0001

< 0.0001

COU-AA-301: Abiraterone Acetate

Improves Overall Survival in mCRPC

HR = 0.646 (0.54-0.77) P < 0.0001

100

Abiraterone acetate:

14.8 months (95%CI: 14.1, 15.4)

80

60

AA

Placebo

40

20

Placebo:

10.9 months (95%CI: 10.2, 12.0)

2 Prior Chemo OS:

14.0 mos AA vs 10.3 mos placebo

1 Prior Chemo OS

15.4 mos AA vs 11.5 mos placebo

0

797

398

100

728

352

200

631

296

300 400 500

Days from Randomization

475

180

204

69

25

8

600

0

1

700

COU-AA-301 Conclusions

AA prolongs OS in patients with mCRPC who have progressed after docetaxel-based chemotherapy

• AA plus prednisone significantly improves TTPP, rPFS, and PSA response rate

– 35% risk reduction of death (HR = 0.65)

– Median OS improvement with AA of 14.8 vs 10.9 months with placebo

– 36% improvement in median OS

– For patients with 1 prior chemo regimen

• Median OS improvement with AA of 15.4 vs 11.5 months with placebo (HR = 0.63)

– Median time to PSA progression and median time to rPFS significantly improved

OS Benefit in Recent CRPC Trials

Trial/

Agent Approved

IMPACT

(Provenge vaccine)

2010

TAX327

(Docetaxel)

2004

TROPIC

(Cabazitaxel)

2010

COU-AA-301

(Abiraterone acetate) 2010

Disease state

Chemonäive

CRPC

Chemo-

CRPC näive

Post-

Docetaxel

CRPC

Post-

Docetaxel

CRPC

Comparator

Placebo

Mitoxantrone

Prednisone

Mitoxantrone

Prednisone

Placebo

Prednisone

Hazard

Ratio

0.775

P value

0.032

0.76

0.70

0.646

0.009

<0.0001

<0.0001

Other prostate highlights

• Roach (UCSF): management of radiation failures

– Various patterns but often isolated local recurrence

– Salvage RT safe and effective

• Scardino: fewer mets with RP than RT. Note: RP→RT salvage 56%; RT→RP salvage 2% AND earlier: 13 months vs 69 months

• Barentsz: imaging

– DCE MRI 92% sensitivity, 85% specificity, NPV 95%, PPV 46% needing biopsy

– 77% of recurrences are in nodes not in CTV

– DWI MRI resolution 5mm, measures restriction of water flow ie nodes look black

– 11 C-choline: resolution ~ 5mm

• Small (UCSF):

– PSADT predicts mortality after RT

Prostate (cont)

Bul (Rotterdam): ERSPC

– 162,387 men, 4-yearly screen, control = standard of care

– PSA cut off = 3.0 then biopsy

– Endpoint: PC mortality

• 9-year followup: mortality decreased 30%

• Rotterdam cohort:

– 42,376 men

– 19,950 screened first round, 15 year followup

– 15,758 initial PSA <3

– 915 = 8.5% PC

– 23 deaths: 5 screen detected, 18 interval

– Mortality increases with higher PSA

• Klotz (Toronto): IADT vs continuous ADT for PSA progression after definitive therapy

– NCIC PR.7: premature stop at interim analysis

– 1386 randomised, 690 IADT, 696 continuous

– IADT: 37.6 no-treatment months, 15.4 on treatment ie 27% on treatment

– OS identical HR 1.02, non-inferiority p 0.009

– Median survival 9 years

– Time to CRPC median 10 years (?)

– Stratify by log rand p=0.024 in favour of IADT but design bias (had to rechallenge in that arm to prove refractory)

– Mortality 18 vs 15%, HR 1.18 p 0.24

– AEs similar re worst events, relate to on-treatment time

– Off treatment QoL data not yet available

Bladder/urothelial

• Gallagher (Dublin): SNPs and chemo sensitivity

– More responses to cisplatin than carboplatin

– MSKCC risk factors: visceral mets Y/N; KPS <80 vs ≥80

• 0: median survival 33 months

• 1: 13 months

• 2: 9 months

– 4 SNPs identified, each scored 0-2 based on allele presence

– Score 0: 80% response; score 8: <30%

– Genes: IL-1β, CCND1 (cyclin D1), PARD6B (cell-cell interaction, insulin signalling), Rs1520896 (chrom 11, gene unknown)

• Case studies:

• “Mixed histology might respond better to MVAC” – not in MDACC data

• GC as neoadjuvant treatment?

• Dose dense MVAC effective (Sternberg)

• GC 7% pathological CR compared to 20-40% MVAC

• RT less effective in extensive CIS

• MMC + 5FU + RT tested in patients with GFR >25 mL/min (James –

UK)

Other bladder/urothelial clinical highlights

• Galsky: cisplatin-ineligible TCC:

• Proposed any of:

PS2 (KPS 60-

70); CrCl <60; CTCAE v4 ≥2 hearing loss or neuropathy; NYHA class III heart failure

• Morales: cisplatin-ineligible TCC:

Gemcitabine 2500 mg/m 2 on day 1 and cisplatin 35 mg/m 2 on day 1, every 14 days. 40 patients, 36 evaluable for response.

– Mean creatinine clearance was 49 mL/min (range:37-59 ml/min)

– Well tolerated overall

One complete response, 14 partial responses (ORR: 42%; 95% CI 27-58%), 11 stable and 10 PD

– Median progression-free survival 15 weeks

Median OS 35 weeks and 1-year OS is 43%

• Other regimens:

• Pagliaro: gemcitabine / paclitaxel / doxorubicin for urothelial cancer and CrCl <60

– G 900 mg/m 2 , P 135, D 40, on d1 q2wk with peg-filgrastim

– 27 pt; 23 assessable for response

• 4 CR and 9 PR = RR 56.5%

• Median OS 13.8 months

• Sridhar: Nab-paclitaxel: 32% PR 53% median PFS 6 months, OS 10.8.

– Increased survival if Hb>100, PS≤1, chemo >5 months ago, get disease control

• Wong: cetuximab/paclitaxel

– C inactive as single agent

– Combo RR 25% with 1 CR and 6 PR in 28 pt

• Smith: carbo/GCB/ABI-007 (nab-pac)

– pCR 27% and get <T2 in 54% ie only non-invasive cancer left

Germ cell

• Not much

• Huddart (Singhera): late CT surveillance in NSGCT

– Relapse ~3% in literature

– Usually metastatic NSGCT, increased AFP, relapses between visits

– Usually require surgery (resect >1cm post chemo)

• Einhorn (Indiana): residual masses

– Do PET wk 6 post chemo: should be negative (SUV <4)

– If positive: consider resection BUT strong desmoplastic reaction after chemo for seminoma

– HR 1.3 for second cancers after RT for seminoma

– 0.4-0.9% leukemia – bladder cancer

– NSGCT:

• They never do RPLND for <1cm nodes

– If >1cm:

• 7% cancer

• 68% teratoma even if no teratoma in primary

• 25% necrosis

– Late relapse usually found by increased AFP (not bhCG) and cured with surgery

(rare cure with chemo alone)

– “NCCN surveillance recommendations excessive”

– Indiana: CT q4mo for 2 yr then q6mo to five years

– Do abdo/pelvis only with CXR; arguably don’t do pelvis

Penile cancer

• Thankfully no horrible brachytherapy photos this year

• Pettaway (MDACC): overview

Bulky primary: penectomy, recurrence <10%

• Might not need 2cm margin

• High grade disease: only 25% have up to 10mm microscopic extension

• Nodes:

– 1-3: 60-80% 5 year DFS

• Controversial to dissect impalpable disease but Dutch study showed good benefit

• Imaging of LN is insensitive

• Surgery then adjuvant RT

Adjuvant chemo for palpable LN:

– Cisplatin/MTX/bleo or VCR/MTX/bleo

• Role for neoadjuvant chemo:

– Cisplatin – taxane/FU/irinotecan etc

– MDACC: paclitaxel/ifosfamide/cisplatin ph2 trial (Pagliaro JCO 2010)

RCC: Wood (MDACC)

• TKIs and surgery

• Various adjuvant studies: ARISER, ASSURE, S-TRAC, SORCE, pazopanib x1yr

• CARMENA French study: non-inferiority sunitinib vs surgery then sunitinib

• Neoadjuvant:

– RR <10% in primary in most series

– Response in primary usually occurs within 60 days

– If no early response there won’t be one

• Tumour thrombus: occasional response, 15% PD; most don’t respond

• (Note: poster showing that response in primary predicts outcome)

• Overall: safe (some dehiscence even late); unreliable at downstaging BUT if see early response then patients do better overall

Atkins (Boston): non-clear-cell RCC

• Papillary do reasonably well in primary but badly when metastatic

• Description of evolution of sarcomatoid RCC subcutaneous metastasis from clear cell primary resistant to sunitinib

– Transplanted into mouse, became clear cell again and restored sensitivity

• Immunotherapy inactive against nccRCC

• Collecting duct:

– Treat as TCC

• Sarcomatoid:

– GCB/doxorubicin: Hass 18% PR

– Sunitinib/sorafenib: PR 9% and only if mostly clear cell with <20% sarcomatoid

– GCB/sunitinib: 3/9 PR but no response if underlying papillary or chromophobe

• Papillary:

– RR 17% with sunitinib, 0% sorafenib

– ARCCS study: sorafenib 23% RR BUT only 3% confirmed responses

– Sunitinib (Gore): PR 11%

– TMS/IFN Dutcher paper Med Oncol 2009: 11.6 mo OS, 7.0 PFS

– HLRCC: FH mutation, increased LDH-A

– HIF-1α mediated, not HIF-2α

• BHD and chromophobe:

– Folliculin mutation

– Activation of mTOR pathway through TSC

Tumour type

Sarcomatoid

PRC1

PRC2

Chromophobe

Collecting duct

Atkins: nccRCC

Primary treatment Possible?

Gem/doxorubicin

? Met inhibitor

?VEGFR inhibitor

?mTOR inhibitor

Local therapy

Carbo/paclitaxel

Sunitinib/GCB

?TMS

?TMS

?erlotinib

LDH-A inhibitor mTOR inhibitor

Gem/cisplatin

RCC: cessation of sunitinib

• Sadegji

• Retrospective analysis: patients with SD or better and then treatment ceased for reasons other than PD

– 40 pt, all clear cell, all had nephrectomy

– Lung and LN mets commonest

– Most on first line therapy

– Time since diagnosis to treatment = 48 months – indolent group?

– Most intermediate Heng risk

– Most on sunitinib, median 14.6mo

– Most had PR, some CR

• Usually ceased because of GI symptoms, then cardiac and vascular events;

15% patient choice

• 25/40 developed PD; 15/40 still SD compared to best prior response, all still on observation

• Of the 25:

– 9/25 treated with sunitinib; 8 continued observation because low volume; 8 had local treatment (RT/surgery)

– Median followup 29.7 mo

– PFS 10 mo (1.4-27.2) in 25 pt

– 7/25 had PD at new site

• Now trial of intermittent sunitinib NCT 01158222

ASCO

• Rini (#4503): axitinib second line vs sorafenib

– 793 pt, after sunitinib / bevacizumab / temsirolimus / cytokine

– Median PFS 6.7 months for axitinib vs 4.7 months, HR 0.665 (P<0.0001)

– Response rates 19.4% for axitinib vs 9.4% for sorafenib (P=0.0001)

• Other inibs: tivozinib, dovitinib

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