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 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

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

LHRHNovel Antiandrogens

AR amplification(30%)

AR mutations?

Intratumoral androgenproduction/conversion

Persistent serumandrogens (eg, adrenals)

Finasteride/DutasterideKetoconazoleAbirateroneAntiandrogens

KetoconazoleAbirateroneSteroidsAntiandrogens

Modified from: Van Allen EM, Ryan CJ. Curr Opinion Urol. 19:315-321. Bonkoff H, Berges R. Prostate. 2010;70:100-112.

CRPC

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

From: Chen Y et al. Curr Opin Pharmacol. 2008;8:440-448.

2. Abirateroneketoconazole

Androgenprecursors

Adrenal synthesis Androgens Cell surfaceligand/receptor

1. 17-AAG

AR degraded

5. TKI inhibitors, antibodies

2. Abirateroneketoconazole

Tumor synthesis

3. 5-reductaseinhibitors

HSP90 DHT

5. Dasatinib

SRCAck1

4. MDV-3100BMS641988

AR

AR AR

AR ARP P

6. HDACi (SAHA, LBH589)

Transcription of TMPRSS-ETS, etcfor growth and survival

AR ARP P

4. MDV-3100BMS641988

Antiandrogens,progestins,

glucocorticoids

mutAR

AmpAR

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, 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

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

AA (n = 797)

Placebo (n = 398)

HR95% CI

P Value

TTPP (months) 10.2 6.6 0.58(0.46, 0.73)

< 0.0001

rPFS (months) 5.6 3.6 0.67(0.59, 0.78)

< 0.0001

PSA response rate

Total 38.0% 10.1% < 0.0001

Confirmed 29.1% 5.5% < 0.0001

COU-AA-301: Abiraterone Acetate Improves Overall Survival in mCRPC

AA 797 728 631 475 204 25 0

Placebo 398 352 296 180 69 8 1

HR = 0.646 (0.54-0.77) P < 0.0001

Placebo: 10.9 months (95%CI: 10.2, 12.0)

0 100 200 300 400 500 600 700

0

20

40

60

80

100

Su

rviv

al (

%)

Days from Randomization

Abiraterone acetate: 14.8 months (95%CI: 14.1, 15.4)

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

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

OS Benefit in Recent CRPC Trials

Trial/Agent Approved

Disease state

ComparatorHazard Ratio

P value

IMPACT(Provenge vaccine) 2010

Chemo-näiveCRPC

Placebo 0.775 0.032

TAX327(Docetaxel) 2004

Chemo-näive CRPC

MitoxantronePrednisone

0.76 0.009

TROPIC(Cabazitaxel) 2010

Post-Docetaxel CRPC

MitoxantronePrednisone

0.70 <0.0001

COU-AA-301(Abiraterone acetate) 2010

Post-DocetaxelCRPC

PlaceboPrednisone

0.646 <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– 11C-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/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

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

Atkins: nccRCCTumour type Primary treatment Possible?

Sarcomatoid Gem/doxorubicin Sunitinib/GCB?TMS

PRC1 ? Met inhibitor ?TMS?erlotinib

PRC2 ?VEGFR inhibitor?mTOR inhibitor

LDH-A inhibitor

Chromophobe Local therapy mTOR inhibitor

Collecting duct Carbo/paclitaxel 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