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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

www.anzup.org.au

2011 ASCO Genitourinary Cancers Symposium

17-19 February 2011, Orlando

http://2011.gucasym.org/

general
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
slide3

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

high points prostate
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
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
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
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
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.

multiple mechanisms of action points of targeted intervention in ar pathways
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.

slide10

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.

cou aa 301 study design
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 abiraterone acetate improves overall survival in mcrpc
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

cou aa 301 conclusions
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

other prostate highlights
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
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
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
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
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
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
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
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
rcc cessation of sunitinib
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
slide26
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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