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2011 ASCO Genitourinary Cancers Symposium 17-19 February 2011, Orlando

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Presentation on theme: "2011 ASCO Genitourinary Cancers Symposium 17-19 February 2011, Orlando"— Presentation transcript:

1 2011 ASCO Genitourinary Cancers Symposium 17-19 February 2011, Orlando

2 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

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

4 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)

5 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

6 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%

7 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 48-82, 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

8 Androgen Resistance: Overlapping mechanisms 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 factor-κB Apoptotic pathways LHRH Novel Antiandrogens AR amplification (30%) AR mutations? Intratumoral androgen production/conversion Persistent serum androgens (eg, adrenals) Finasteride/Dutasteride Ketoconazole Abiraterone Antiandrogens 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. CRPC

9 Multiple mechanisms of action: points of targeted intervention in AR pathways From: Chen Y et al. Curr Opin Pharmacol. 2008;8:440-448.

10 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 identifier: NCT00638690.

11 COU-AA-301 study design Phase 3, multinational, multicenter, randomized, double-blind, placebo- controlled 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 identifier: NCT00638690

12 COU-AA-301: All Secondary End Points Achieved Statistical Significance AA (n = 797) Placebo (n = 398) HR 95% CI P Value TTPP (months) (0.46, 0.73) < 0.0001 rPFS (months) (0.59, 0.78) < 0.0001 PSA response rate Total38.0%10.1%< 0.0001 Confirmed29.1%5.5%< 0.0001

13 COU-AA-301: Abiraterone Acetate Improves Overall Survival in mCRPC AA 797728631475204250 Placebo3983522961806981 HR = 0.646 (0.54-0.77) P < 0.0001 Placebo: 10.9 months (95%CI: 10.2, 12.0) 0 100200 300 400 500 600700 0 20 40 60 80 100 Survival (%) Days from Randomization Abiraterone acetate: 14.8 months (95%CI: 14.1, 15.4) 2 Prior Chemo OS: 1 Prior Chemo OS 14.0 mos AA vs 10.3 mos placebo 15.4 mos AA vs 11.5 mos placebo 0

14 COU-AA-301 Conclusions 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 AA prolongs OS in patients with mCRPC who have progressed after docetaxel-based chemotherapy

15 OS Benefit in Recent CRPC Trials Trial/ Agent Approved Disease state Comparator Hazard Ratio P value IMPACT (Provenge vaccine) 2010 Chemo-näive CRPC Placebo0.7750.032 TAX327 (Docetaxel) 2004 Chemo-näive CRPC Mitoxantrone Prednisone 0.760.009 TROPIC (Cabazitaxel) 2010 Post- Docetaxel CRPC Mitoxantrone Prednisone 0.70<0.0001 COU-AA-301 (Abiraterone acetate) 2010 Post- Docetaxel CRPC Placebo Prednisone 0.646<0.0001

16 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

17 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

18 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)

19 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

20 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

21 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)

22 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

23 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

24 Atkins: nccRCC Tumour typePrimary treatmentPossible? SarcomatoidGem/doxorubicinSunitinib/GCB ?TMS PRC1? Met inhibitor?TMS ?erlotinib PRC2?VEGFR inhibitor ?mTOR inhibitor LDH-A inhibitor ChromophobeLocal therapymTOR inhibitor Collecting ductCarbo/paclitaxelGem/cisplatin

25 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

26 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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