1 / 26

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

tracy
Download Presentation

2011 ASCO Genitourinary Cancers Symposium

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related