Transcript Ian Davis presentation

2011 ASCO Genitourinary
Cancers Symposium
17-19 February 2011, Orlando
http://2011.gucasym.org/
www.anzup.org.au
General
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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
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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
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Day 3: Renal
– General Session VII: Renal Cancer
– General Session VIII: Translational Science Session: Renal Cancer^
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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:
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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
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Background and rationale: to determine if long term antiandrogen therapy with RT improves
cancer control and OS
Design:
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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
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Stratification: margins; nadir PSA < 0.5; entry PSA < 1.5; neoadjuvant short term ADT
Primary endpoint: OS
Demographics:
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Note: not current treatment regimen
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:
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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
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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
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Note: D shrinks gland so more likely to find any residual cancer
Note: FDA warning issued 9 June 2011
Androgen Resistance:
Overlapping mechanisms
Finasteride/Dutasteride
Ketoconazole
Abiraterone
Antiandrogens
LHRH
Novel
Antiandrogens
AR amplification
(30%)
AR mutations?
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
Intratumoral androgen
production/conversion
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
2. Abiraterone
ketoconazole
Adrenal synthesis
Androgen
precursors
Androgens
Cell surface
ligand/receptor
5. TKI inhibitors,
antibodies
Tumor synthesis
1. 17-AAG
AR
AR degraded
HSP90
mut
AR
Amp
AR
3. 5-reductase
inhibitors
DHT
Ack1
2. Abiraterone
ketoconazole
AR
4. MDV-3100
BMS641988
AR
P
Antiandrogens,
progestins,
glucocorticoids
4. MDV-3100
BMS641988
From: Chen Y et al. Curr Opin Pharmacol. 2008;8:440-448.
SRC
AR
5. Dasatinib
AR
P
6. HDACi (SAHA, LBH589)
P
AR
AR
P
Transcription of TMPRSS-ETS, etc
for growth and survival
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
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Phase 3, multinational, multicenter, randomized, double-blind, placebocontrolled study (147 sites in 13 countries; USA, Europe, Australia, Canada)
Primary end point:
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Secondary end points:
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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:
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25% improvement in overall survival (HR = 0.8)
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)
HR
95% 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
Total
38.0%
10.1%
< 0.0001
Confirmed
29.1%
5.5%
< 0.0001
PSA response rate
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)
Survival (%)
80
60
40
Placebo:
10.9 months (95%CI: 10.2, 12.0)
20
2 Prior Chemo OS:
14.0 mos AA vs 10.3 mos placebo
1 Prior Chemo OS
15.4 mos AA vs 11.5 mos placebo
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0
100
200
300
400
500
600
Days from Randomization
AA
797
728
631
475
204
25
0
Placebo
398
352
296
180
69
8
1
700
COU-AA-301 Conclusions
AA prolongs OS in patients with mCRPC who have
progressed after docetaxel-based chemotherapy
• 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
OS Benefit in Recent CRPC Trials
Trial/
Agent Approved
Disease
state
Comparator
Hazard
Ratio
P value
IMPACT
(Provenge
vaccine)
2010
Chemo-näive
CRPC
Placebo
0.775
0.032
TAX327
(Docetaxel)
2004
Chemo-näive
CRPC
Mitoxantrone
Prednisone
0.76
0.009
TROPIC
(Cabazitaxel)
2010
PostDocetaxel
CRPC
Mitoxantrone
Prednisone
0.70
<0.0001
COU-AA-301
(Abiraterone
acetate) 2010
PostDocetaxel
CRPC
Placebo
Prednisone
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)
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Bul (Rotterdam): ERSPC
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9-year followup: mortality decreased 30%
Rotterdam cohort:
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162,387 men, 4-yearly screen, control = standard of care
PSA cut off = 3.0 then biopsy
Endpoint: PC mortality
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
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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
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Galsky: cisplatin-ineligible TCC:
Proposed any of:
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Morales: cisplatin-ineligible TCC:
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PS2 (KPS 60-70); CrCl <60; CTCAE v4 ≥2 hearing loss or neuropathy; NYHA class III heart failure
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
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G 900 mg/m2, P 135, D 40, on d1 q2wk with peg-filgrastim
27 pt; 23 assessable for response
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Sridhar: Nab-paclitaxel: 32% PR 53% median PFS 6 months, OS 10.8.
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Increased survival if Hb>100, PS≤1, chemo >5 months ago, get disease control
Wong: cetuximab/paclitaxel
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4 CR and 9 PR = RR 56.5%
Median OS 13.8 months
C inactive as single agent
Combo RR 25% with 1 CR and 6 PR in 28 pt
Smith: carbo/GCB/ABI-007 (nab-pac)
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pCR 27% and get <T2 in 54% ie only non-invasive cancer left
Germ cell
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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)
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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
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Thankfully no horrible brachytherapy photos this year
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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
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Controversial to dissect impalpable disease but Dutch study showed good
benefit
Imaging of LN is insensitive
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Surgery then adjuvant RT
Adjuvant chemo for palpable LN:
– Cisplatin/MTX/bleo or VCR/MTX/bleo
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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
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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
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Immunotherapy inactive against nccRCC
Collecting duct:
– Treat as TCC
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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
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Papillary:
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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: nccRCC
Tumour 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
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Sadegji
Retrospective analysis: patients with SD or better and then treatment ceased for
reasons other than PD
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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
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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