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2011 ASCO Genitourinary Cancers Symposium

www.anzup.org.au. 2011 ASCO Genitourinary Cancers Symposium. 17-19 February 2011, Orlando http://2011.gucasym.org/. General. Approximately 500 participants, seemed more Program: Day 1: Prostate

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2011 ASCO Genitourinary Cancers Symposium

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  1. www.anzup.org.au 2011 ASCO Genitourinary Cancers Symposium 17-19 February 2011, Orlando http://2011.gucasym.org/

  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 Finasteride/Dutasteride Ketoconazole Abiraterone Antiandrogens LHRH Novel Antiandrogens Intratumoral androgen production/conversion AR amplification (30%) AR mutations? CRPC 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.

  9. Multiple mechanisms of action: points of targeted intervention in AR pathways 2.Abirateroneketoconazole Cell surfaceligand/receptor Adrenal synthesis Androgenprecursors Androgens 5. TKI inhibitors, antibodies Tumor synthesis 1. 17-AAG AR 3.5-reductaseinhibitors 2.Abirateroneketoconazole Ack1 SRC AR degraded DHT HSP90 4. MDV-3100BMS641988 5. Dasatinib mutAR AR AR P P AR AR Antiandrogens,progestins,glucocorticoids 6. HDACi (SAHA, LBH589) AmpAR Transcription of TMPRSS-ETS, etcfor growth and survival P P AR AR 4.MDV-3100BMS641988 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 ChemotherapyPrior Chemotherapy Prednisone Add-on Therapy Clinicaltrials.gov 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 Clinicaltrials.gov identifier: NCT00638690

  12. COU-AA-301: All Secondary End Points Achieved Statistical Significance

  13. 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 Survival (%) 40 Placebo: 10.9 months (95%CI: 10.2, 12.0) 20 2 Prior Chemo OS: 1 Prior Chemo OS14.0 mos AA vs 10.3 mos placebo 15.4 mos AA vs 11.5 mos placebo 0 0 300 500 0 400 600 700 100 200 Days from Randomization

  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

  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 • 11C-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/m2 on day 1 and cisplatin 35 mg/m2 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/m2, 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

  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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