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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


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 Therapy: Oncogene and Non-oncogene Addiction. Cell 136:823-837, 2009

  • 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 Therapy: Oncogene and Non-oncogene Addiction. Cell 136:823-837, 2009

  • 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 Therapy: Oncogene and Non-oncogene Addiction. Cell 136:823-837, 2009

  • 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 Therapy: Oncogene and Non-oncogene Addiction. Cell 136:823-837, 2009

  • 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: Therapy: Oncogene and Non-oncogene Addiction. Cell 136:823-837, 2009Overlapping 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.


Study 301 Phase 3: intervention in AR pathwaysRandomized, 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 intervention in AR pathways

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 mCRPCConclusions

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 mCRPC

  • 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) mCRPC

  • 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 mCRPC

  • 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 mCRPC

  • 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 mCRPC

  • 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 mCRPC

  • 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) mCRPC

  • 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 mCRPC

  • 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 mCRPC

  • 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 mCRPC

  • 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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