update on the treatment of prostate cancer
DESCRIPTION
Update on the Treatment of Prostate Cancer. David M. Nanus, MD Chief, Division of Hematology and Medical Oncology Weill Medical College of Cornell University New York Presbyterian Hospital. Demographics. 238,590 estimated new cases in 2013 - 27.9% of all cancers in males - PowerPoint PPT PresentationTRANSCRIPT
Update on the Treatment of Prostate Cancer
David M. Nanus, MD
Chief, Division of Hematology and Medical Oncology
Weill Medical College of Cornell University
New York Presbyterian Hospital
Demographics
238,590 estimated new cases in 2013- 27.9% of all cancers in males- most common cancer in men- Lifetime risk: 16% (1 in 6)
29,720 estimated deaths- 9.7% of cancer deaths in males- second to lung cancer in men
ClinicallyLocalizedDisease
RisingPSA
ClinicalMetastases
Non-Castrate
CastrateRisingPSA
CastrateMetastaticDisease
Death from other causes Death fromProstate cancer
Adapted from Scher et al.
PSA – Like a Clint Eastwood Movie
The Good
PSA-based early detection decreases mortality
The Bad
Not perfectly sensitive or specific
Over-detection compounded by Over-treatment
The Ugly
Treatment arbitrary, variable, often unnecessary and increasingly costly
Screening Recommendations
Shared decision making Annual PSA and DRE
- from age of 40 (AUA); age 50 (ACS)- High risk: 40-45 (African American; 1rst degree relative)
Frequency- AUA: annually (based on initial PSA)- ACS: annually (every 2 year if PSA < 2.5 ng/ml)
Discontinue: life expectancy <10 years
Significance of cancer:Determining need for treatment
Patient (age, comorbidities) Gleason score
- sum of two predominant areas
Tumor characteristics- Number of positive cores
- Percent positive within each core
Molecular profile
Active Surveillance
Surveillance in low risk patients is feasible and associated with a limited risk of progression
Progression can be quantitated
Predictors of progression and treatment can be identified
Screening results in the detection of very early stage/grade lesions - many indolent
Current staging/grading techniques accurate
Natural history prolonged and can be measured
Rationale Hypotheses
Intervention
62% free of intervention at 10 y
Surveillance Survival (years)
Su
rviv
al d
istr
ibu
tion
fu
nct
ion
0 2 4 6 8 10 12 14
0.0
0.2
0.4
0.6
0.8
1.0
Klotz L, et al. J Clin Oncol 2010;26:126–31
Overall Survival (years)
Su
rviv
al d
istr
ibu
tion
fu
nct
ion
0 2 4 6 8 10 12 14
0.0
0.2
0.4
0.6
0.8
1.0
Overall Survival
N=452
Ca-Specific Survival
5/452 patients
All PSADT ≤ 1.6 years
97% at 10 years
Defining the Triggers for Intervention
• Change in PSA kinetics: PSADT <3 y
• Progression on follow-up biopsy• Increase in Gleason grade
• Increase in tumor volume– Increase in absolute cores involved with cancer– Increase in percent of positive cores >33%– Increase in absolute tumor length (mm)– Increase in percent of tumor tissue >50% within single core
• Patient preference
• Clinical/radiographic evidence of local/distant progression
What’s new in prostate cancer therapy?
Targeting the androgen axis Immunotherapy Chemotherapy Bone targeted therapies
Molecular genetics Circulating prostate cancer tumor cells
Intermittent versus continuous androgen deprivation in hormone sensitive metastatic prostate cancer patients:
Results of S9346 (INT-0162), An international phase III trial
3040 hormone naïve metastatic patients- PS 0-2- PSA ≥ 5 ng/ml- treated with 7 months of goserelin + bicalutamide
1535 pts PSA ≤4 ng/ml- randomized to CAD or IAD
Primary objective: non-inferior Median Follow up: 10 years
Management of Castrate Resistant Metastatic Prostate Cancer
Androgen Signaling Axis Therapy- Abiraterone- Enzalutamide (MDV3100)
Chemotherapy- Docetaxel- Cabazitaxel- Mitoxantrone
Bone Targeted- Radium-223
Adapted from Harris et al. Nature Reviews Clin Onc 2009
Intra-cellular androgenAlternatively-spliced AR
cholesterol
pregnenolone
17α-hydroxy-pregnenolone
DHEAandrostenedione
TestosteroneDHT
CYP17
CYP17
Mineralocorticoids
Cortisol
Simplified view of cholesterol testosterone synthesis
Occurs in: Testes, Adrenal Gland, Prostate cancer cells
Montgomery et al. Cancer Res 2008Locke et al. Cancer Res
cholesterol
pregnenolone
17α-hydroxy-pregnenolone
DHEAandrostenedione
TestosteroneDHT
CYP17
CYP17
Mineralocorticoids
Cortisol
Montgomery et al. Cancer Res 2008Locke et al. Cancer Res
AbirateroneAcetate
Oral irreversible inhibitor of CYP17
- 17α –hydroxylase
- C17,20-lyase Inhibits testosterone
production in testis, adrenal, and prostate
Overall survival HR=hazard ratio. AA=abiraterone acetate. P=prednisone.
COU-AA-301Abiraterone Acetate + prednisone vs Placebo + prednisonein men with progressive metastatic CPRC after docetaxel
Fizazi et al. Lancet Oncol 2013;13:983.de Bono JS et al. N Engl J Med 2011;364:1995-2005.
Hazard Ratios for the Risk of Death, According to Subgroup
de Bono JS et al. N Engl J Med 2011;364:1995-2005.
Chemo-naïve CRPC (n=1088)
Asymptomatic or mildly symptomatic
Abiraterone 1000 mg/dPrednisone mg bid
Placebo dailyPrednisone mg bid
Primary endpoint: Radiographic PFS, OSSecondary endpoints: Time to – opiate use; chemotherapy; EOCS-PS deterioration; progression
COU-AA-302
Prednisone Abiraterone + Prednisone
Radiographic PFS
8.3 mos 16.5 mos HR 0.53; p < 0.0001
Overall Survival 30.1 mos 35.3 mos HR 0.79;p = 0.0151*
> 50% PSA decline
69% 29%
Median Time to Chemotherapy
16.8 mos 26.5 mos HR: 0.61p < 0.0001
Median Time to Opiate Use
23.7 mos NR HR 0.71p = 0.0002
COU-AA-302: Updated interim results
* did not cross the prespecified boundary for significance (p = 0.0035)
Ryan CJ et al. N M2013;368:138-148 + GU ASCO 2013
Subgroup Analyses of Hazard Ratios for Death in the Two Study Groups
Scher HI et al. N Engl J Med 2012;367:1187-1197.
Enzalutamide
• PREVAIL trial: Phase 3 CRPC before chemotherapy
• TERRAIN trial: Phase 2 comparing Enzalutamide with bicalutamide in men who have progressed on LHRH analogue therapy or following surgical castration
Other studies:Enzalutamide + docetaxel
Enzalutamide + abiraterone
Immunotherapy
Cancer vaccines Modulation of immune regulatory mechanisms
- Blocking CTLA-4- Blocking PD-1 or PDL-1
Monoclonal antibody targeting of tumour growth
IMPACT Trial
HR=0.759 (95% CI: 0.606, 0.951)P=.017 (Cox model)
Median Survival Benefit: 4.1 months
Sipuleucel-T (n=341)Median Survival: 25.8 months
36-months survival: 32.1%
Control (n=171)Median Survival: 21.7 months
36-months survival: 23.0%
Kantoff et al, ASCO GU 2010
Radium-223 Targets Bone Metastases
Radium-223 acts as a calcium mimic
Naturally targets new bone growth in and around bone metastases
Radium-223 is excreted by the small intestine
Ra
Ca
Parker et al; ECCO-ESMO 2011
TREATMENT
6 injections at 4-week intervals
Radium-223 (50 kBq/kg) + Best standard of care
Radium-223 (50 kBq/kg) + Best standard of care
Placebo (saline) + Best standard of care
Placebo (saline) + Best standard of care
N = 922
PATIENTS
• Confirmed symptomatic
CRPC
• ≥ 2 bone metastases
• No known visceral
metastases
• Post-docetaxel or unfit for docetaxel
• Confirmed symptomatic
CRPC
• ≥ 2 bone metastases
• No known visceral
metastases
• Post-docetaxel or unfit for docetaxel
ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design
Clinicaltrials.gov identifier: NCT00699751.
• Total ALP: < 220 U/L vs ≥ 220 U/L• Bisphosphonate use:
Yes vs No• Prior docetaxel:
Yes vs No
• Total ALP: < 220 U/L vs ≥ 220 U/L• Bisphosphonate use:
Yes vs No• Prior docetaxel:
Yes vs No
STRATIFICATION
Parker et al; ECCO-ESMO 2011
RANDOMISED
2:1
Month 0 3 6 9 12 15 18 21 24 27
Radium- 223 541 450 330 213 120 72 30 15 3 0
Placebo 268 218 147 89 49 28 15 7 3 0
ALSYMPCA Overall Survival
00
1010
2020
3030
4040
5050
6060
7070
8080
9090
100100
% %Radium-223, n = 541
Median OS: 14.0 monthsRadium-223, n = 541
Median OS: 14.0 months
Placebo, n = 268Median OS: 11.2 months
Placebo, n = 268Median OS: 11.2 months
HR 0.695; 95% CI, 0.552-0.875
P = 0.00185HR 0.695; 95% CI, 0.552-0.875
P = 0.00185
Parker et al; ECCO-ESMO 2011
Increase in median survival
Relative reduction in risk of death
Hazard ratio (95% CI; P-value)
Abiraterone/P vs. placebo/P
3. 9 mos 35% 0.65 (0.54-0.77; P<0.001)
Enzalutamide vs. placebo
4.8 mos 37% 0.63(P<0.0001)
Docetaxel(q3w)/P vs. Mitoxantrone/P
2.4 mos 24% 0.76 (0.62-0.94; P=0.009)
Cabazitaxel/P vs. mitoxantrone/P
2.8 mos 30% 0.70 (0.59-0.83; P<0.0001)
Sipuleucel T vs. placebo
4.1 mos 22% 0.78 (0.61- 0.98;P:0.03)
Alpharadin vs. placebo
2.8 mos 31% 0.70 (0.55-0.88; P:0.00185)
CRPC Therapeutic Options
Trial Name Arm B: DocPred plus Mechanism
ASCENT-2 DN101 Calcitriol
CALGB 90401 Bevacizumab VEGF
SWOG 0421 Atrasentan Endothelin receptor antagonist
MAINSAIL Lenalinomide Anti-angiogenic; immune
VENICE Aflibercept Soluble VEGF fusion protein
ENTHUSE 33 Zibotentan Endothelin receptor antagonist
READY Dasatinib SRC kinase inhibitor
SYNERGY OGX-11 Antisense to clusterin (cell survival protein)
FIRSTANA vs. Cabazitaxel (unTxed)
Taxane Chemotherapy
Phase III Randomized Trials vs. Docetaxel + PrednisonePrimary Endpoint: Overall Survival
Molecular Markers
Beyond the microscope May be diagnostic, prognostic, and/or predictive Gene fusions
TMRPSS2-ERG
Expression of abnormal proteinsMany may be targetable
Circulating Tumor Cells (CTCs)
Frequency Therapy
Ets gene fusion 50-60% PARP inhibitor
PTEN/MAGI2 25-40% PI3K inhibitor
BRAC2/ATM 20% PARP inhibitor
Spink1 10-15% EGFr inhibitor
Aurora kinase A 5-40% AURK inhibitor
SPOP 10% ?
BRaf fusion 1% Raf inhibitor
Frequency Therapy
Ets gene fusion 50-60% PARP inhibitor
PTEN/MAGI2 25-40% PI3K inhibitor
BRAC2/ATM 20% PARP inhibitor
Spink1 10-15% EGFr inhibitor
Aurora kinase A 5-40% AURK inhibitor
SPOP 10% ?
BRaf fusion 1% Raf inhibitor
Neuroendocrine or anaplastic prostate cancer
Multi-institutional Phase II Trial of The Aurora kinase A inhibitor MLN8237 for Patients with Neuroendocrine Prostate Cancer
Inclusion Criteria: - Pathologic diagnosis
- Clinical diagnosis: visceral metastases in absence of PSA progression, elevated serum neuroendocrine marker
MLN8237 50 mg bid orally x 7 d on 21 day cycle Molecular biomarkers
- Tumor biopsies
- CTC analyses
- Exome/transcriptome sequencing
RANDOMIZE
2:1
100 men with Chemotherapy naïve metastaticCRPC
TAXSYNERGY: Phase II Trial to Evaluate Benefit of Early Switch from first-Line Docetaxel/Prednisone to Cabazitaxel/Prednisone and the opposite sequence,
exploring molecular markers and mechanisms of taxane resistance in men with Metastatic mCRPC who have not received prior chemotherapy
Docetaxel 75 mg/m2
Cabazitaxel 25 mg/m2
4 cycles
>30% PSA reduction
<30% PSA reduction
>30% PSA reduction
<30% PSA reduction
Docetaxel Continued
CabazitaxelContinued
Switch to Cabazitaxel
Switch to Docetaxel
Primary Objective: Explore benefit of an early switch from DOC to CBZEvaluate the association of biomarkers with clinical response/resistance to Rx
- Molecular Drug Target Engagement (DTE) in CTCs - RNA sequencing on CTCs to assess for tubulin mutations and AR isoforms
RANDOMIZE
2:1
100 men with Chemotherapy naïve metastaticCRPC
Docetaxel 75 mg/m2
Cabazitaxel 25 mg/m2
4 cycles
>30% PSA reduction
<30% PSA reduction
>30% PSA reduction
<30% PSA reduction
Docetaxel Continued
CabazitaxelContinued
Switch to Cabazitaxel
Switch to Docetaxel
GEDI CTCs
Baseline: Multiplex confocal, AR Taqman variant, RNA-Seq, ex-vivo predictive assaysCycle 1/Day 8 : Multiplex confocal (enumeration; AR subcellular localization; endogenous DTE)C4 Crossover :Mutliplex confocal, AR Taqman variant, ex-vivo predictive assaysC5/Day 8: Multiplex confocal Relapse: Mutliplex confocal, AR Taqman variant, RNA-Seq
Eligibility:> 1 bone metastasis, ADT therapy within 6 mos of enrollment
Therapy:Zoledronic acid or placebo q 4 weeks
Median time to first SRE (skeletal-related event)32.5 vs 29.8 mos (HR = 0.96 [0.76-1.22]; P=0.74)
> Grade 3 toxicity same (15% vs. 12% in ZA and P)
Overall survival (HR= 0.89 [0.70-1.14]; P=0.34)
CALGB 90202: A Randomized, Double-Blind, Placebo-Controlled Phase III Study of Early versus Standard Zoledronic Acid (ZA) to Prevent Skeletal
Related Events in Men with Prostate Cancer Metastatic to Bone
Smith MR et al. 2013 GU Cancers Symposium
Targeted Therapy: Denosumab vs zoledronic acid for Skeletal Related Events risk-reduction in CRPC
Fizazi et al, Lancet 2011; 377: 813
Management of Metastatic CRPCSequencing???
Chemotherapy- Docetaxel, Cabazitaxel, Mitoxantrone
Androgen Signaling Axis Therapy- Abiraterone- Enzalutamide
Bone Targeted- Denosumab- Alpharadin
Smith D C et al. JCO 2013;31:412-419
Cabozantinib (XL184): orally bioavailable tyrosine kinase inhibitoragainst MET and VEGFr2 in men with CRPC
PFS in (A) randomly assigned patients with CRPC; and (B) patients with CRPC by docetaxel pretreatment status
Smith D C et al. JCO 2013;31:412-419
Where We Are Now: Positive Phase 3 Trials in Met CRPCTrial Design HR Endpoint Comment
CanadianN = 161
Mitoxantrone/prednisone vsprednisone
NR Palliation in 29% vs 12% (duration 42 vs
18 wks)
Approval of mitoxantrone (also CALGB 9182)
TAX 327N = 1006
Docetaxel/prednisone vs mitoxantrone/prednisone
0.76 OS 18.9 vs 16.5 mo
Docetacel/pred approved as new standard
SWOG 9916N = 770
Docetaxel/estramustine vs mitoxantrone/prednisone
0.80 OS 17.5 vs 15.6 mo
Support docetaxel as new standard
ZAPCSGN = 643
Zoledronic acid vs placebo NR SRE 33.2% vs 44.2%
Zoledronic acid reduces SRE’s
IMPACT N = 512
Sipuleucel-T vs Control 0.78 OS 25.8 vs 21.7 mo
Sip-T approved min symptomatic metCRPC
Dmab 103N = 1904
Denosumab vs zoledronic acid 0.82 SRE-free 20.7 vs 17.1 mo
Denosumab approved
TROPICN = 755
Cabazitaxel/prednisone vs mitoxantrone/prednisone
0.70 OS 15.1 vs 12.7 mo
Cabazitaxel approved post-docetaxel
COU-AA-301N = 1195
Abiraterone/prednisone vsPlacebo/prednisone
0.65 OS 14.8 vs 10.9 mo
Abi/pred approved post-docetaxel
ALSYMPCAN = 922
Radium-223/BSC vs placebo/BSC 0.70 OS 14.0 vs 11.2 mo
Pending approval
AFFIRMN=1199
Enzalutamide vs Placebo 0.63 OS 18.4 vs 13.6 mo
Enzalutamide approved post-docetaxel
COU-AA-302N = 1088
Abiraterone/prednisone vsPlacebo/prednisone
0.43 16.5 mos vs 8.3 mo
Strong trend for OS