Board Review 2017: Prostate Cancer Dana Rathkopf, MD Associate Attending www.mskcc.org
The Paradox of Prostate Cancer High prevalence in the general population: over diagnosis of clinically insignificant cancers is a concern. Can be less lethal to a patient than existing comorbidities but remains the 2nd leading cause of cancer death in men. A natural history that can span 10 years or more, for which treatment can often be deferred at diagnosis or relapse.
Willet Whitmore, Jr., MD Chief of the Urology Service, 1952-1983 Memorial Sloan-Kettering Cancer Center Is cure possible when it is necessary? Is cure necessary when it is possible?
Cancer Statistics, United States Most common malignancy in men other than skin cancer: -1 man in 7 will be diagnosed with prostate cancer -66 is median age of diagnosis Third leading cause of cancer related death in men: -1 man in 39 will die of prostate cancer - 1 man in 6 diagnosed with prostate cancer will die from the disease Siegal R CA Cancer J Clin 2017
Incidence and Mortality Rates from Prostate Cancer are Declining Cancer Incidence, Males Cancer Deaths, Males 1994: PSA approved by the FDA to aid in cancer detection 2011: USPSTF recommends against routine PSA screening 2010-2013: prostate cancer incidence has dropped >10% annually Siegal R CA Cancer J Clin 2017
Risk Factors and Prevention
Prostate Cancer Risk Factors Age: Six in 10 cases of prostate cancer are found in men older than 65 (median age 66). Ethnicity: African-American men have the highest incidence of diagnosis and are twice as likely to die of their disease. Geography: Most common in North America, northwestern Europe, Australia, and on Caribbean islands. Family History: Higher risk is associated with brother > father with prostate cancer (2x), multiple family members with prostate cancer (especially if < 55 at diagnosis). Inherited Gene Changes: BRCA2>BRCA1, Lynch Syndrome (HNPCC) American Cancer Society https://www.cancer.org/cancer/prostate-cancer
Selenium and Vitamin E Prevention Trial (SELECT) HR 1.17 CI, 1.04-1.36 P=.008 Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men Klein, EA JAMA. 2011
Prostate Cancer Prevention Trial (PCPT): 5 alpha reductase inhibitor N=18,880 Placebo vs. finasteride Detected Prostate Cancer in 18.4% finasteride vs 24.8% placebo; benefit associated entirely with reduced risk of low grade prostate cancer Did not protect against high grade prostate cancer (HR 1.17) No benefit in OS Thompson I, NEJM 2003, 2013 15 year OS rate no different between the two
Molecular Pathogenesis and Progression Enzalutamide Schrecengost R and Knudsen K, Seminars in Oncology, 2013
Early Detection, Diagnosis and Staging
Screening Recommendations The ACS, AUA and NCCN recommend that men should first be informed of the risks and potential benefits of screening, then offered PSA and DRE beginning at age 50 years and continuing annually as long as they have a life expectancy > 10 years. The discussion should take place at age 45 for men at high risk (African Americans, those with a family history) and at age 40 for very high risk men (several first degree relatives).
Screening for Prostate Cancer U. S. Preventive Services Task Force (USPSTF) http://www.uspreventiveservicestaskforce.org
Does PSA screening reduce prostate cancer mortality? PLCO: No n=76,693 ERSPC: Yes n=182,160 HR= 0.8 95% CI, 0.65-0.98 P=0.04 To prevent one prostate-cancer death, 1410 men screened, 48 treated.
Prostate Cancer Pathology Grade Groups The five-year biochemical recurrence-free progression probabilities for radical prostatectomy Grade Groups 1-5 were 96%, 88%, 63%, 48%, and 26%. Epstein JI, A contemporary prostate cancer grading system: A validated alternative to the Gleason score. Eur Urol (2016).
Prostate Cancer Staging
Prostate Cancer Clinical States HORMONE-SENSITIVE Diagnosis 161, 360 Clinically Localized Disease Biochemical Recurrence (PSA) Active Surveillance Intermitten t ADT Surgery Metastatic Docetaxel 2015 Radiation +/- ADT Continuous ADT CASTRATION -RESISTANT Deaths From Disease 26, 730 NonMetastatic Metastatic First-Line Treatment Metastatic Post-Chemo Docetaxel 2004 Cabazitaxel 2010 Sipuleucel -T 2010 Abiraterone 2011 Abiraterone 2012 Enzalutamide 2012 Enzalutamide 2014 Alpharadin 2013 Olaparib 2016
Treatment of Localized Disease
Primary Androgen Deprivation Therapy (PADT) Not recommended. PADT should not be used as monotherapy in clinically localized prostate cancer NCCN 2016 Potosky JCO 2014 15,170 pt s on cancer registries No survival advantage for PADT Lu, JAMA Int Med 2014 66,717 Medicare No OS benefit PADT
ADT considerations NOT curative Sexual dysfunction Obesity Osteoporosis DVT Cognitive effects Cardiac Risk: - 5 studies demonstrated increased cardiac side effects of ADT* - Large meta-analysis showed no increased risk (Nguyen JAMA 2011) *Keating J Clin Oncol. 2006; D Amico J Clin Oncol. 2007; D Amico JAMA. 2008; Saigal CS Cancer. 2008; Tsai HK J Natl Cancer Inst. 2007.
SPCG-4 Trial N = 695 0.75 (95% CI, 0.61 to 0.92; P = 0.007) 0.62 (95% CI, 0.44 to 0.87; P = 0.01) 0.59 (95% CI, 0.45 to 0.79; P<0.001 0.56 (95% CI, 0.41 to 0.77; P = 0.001)* NNT to prevent one death = 8 Median of 13.4 years follow-up, most benefit from RP in men < 65 and intermediate risk PC *Bill-Axelson A N Eng J Med, 2014- Extended follow-up 23.2 years
PIVOT TRIAL N=731 Wilt TJ, et al.,n Engl J Med 2012. Bone Metastases Death from Any Cause HR 0.88 95% CI, 0.71-1.08 P=0.22 Death from Prostate Cancer HR 0.40; 95% CI, 0.22-0.70; P<0.001 HR 0.63 95% CI, 0.36-1.09 P=0.09 Radical prostatectomy did not significantly reduce all-cause or prostate cancer specific mortality
ProtecT PSA: 82,429 PC: 2664 Randomized: 1643 At a median of 10 years, PCSM was low irrespective of treatment assigned. Surgery and RT associated with lower incidences of disease progression and metastases Hamdy FC N Engl J Med 2016
5 Years: RP 5x > incontinence, RP 2x > erectile dysfunction Consistent functional decline in both arms after 5 years 15 years: no significant difference in functional outcomes Resnick MJ N Engl J Med 2013
Treatment of High-Risk Disease: What is Risk? Category Definition Surveillance? Very low T1c, Gleason score 6, PSA < 10, fewer than 3 cores positive, 50% involved in each core, PSA density <0.15 ng/ml/g Life expectancy: <20 years Low T1-2a, Gleason score 6, PSA < 10 <10 years Intermediate T2b-c OR Gleason score 7 OR PSA 10-20 <10 years High T3a OR Gleason score 8 OR PSA >20 Not specified Very high (locally advanced) T3b-4 Not specified Metastatic Any nodal or distant metastasis NCCN 2016
High risk disease: Radiation therapy and ADT N Patients ADT, months Positive Result (Primary Endpoint) EORTC 22863 (1997, 2010) 412 T3-4, GR 3 WHO 36 vs. 0 OS RTOG 8531 (1997, 2005) 997 T3 or N+ Lifelong vs. 0 OS for Gl 7-10 RTOG 8610 (1995, 2001, 2008) 456 T2-4 or N+ 4 vs. 0 OS did not hit, except low grade disease; DSS TROG 9601 (2005, 2011) 818 T2b-4; N0 0 vs. 3 vs. 6 OS for 6 mo arm only RTOG 9202 (2003, 2008) 1554 T2c-4, N0 28 vs 4 OS for Gl 8-10 EORTC 22961 (2009) 970 T2c-4, N+ 36 vs 6 OS Canada PCS IV (ASCO 2013) 630 T3 or PSA>20 or Gl 8, N0 36 vs. 18 No difference
RRP and Adjuvant ADT in Node Positive Disease Pre-PSA Era (prospective) N=98 Messing, Lancet Oncol, 2006 PSA era (retrospective) N=731 Wong, J Clin Oncol, 2009
RRP and Adjuvant RT in High Risk Disease EORTC 22911 Bolla (Lancet 2012) SWOG 8794 Thompson (J Urol 2009) ARO 9602 Wiegel (JCO 2009, GU ASCO 2013) Eligibility pt2-3n0 ece, svi, or margin+ pt2-3n0 ece, svi, or margin+ pt3n0 ece, svi, or margin+ N n=1005 30% PSA >0.2 ng/ml n=425 33% PSA >0.2 ng/ml n=307 20% PSA >0.1 ng/ml Follow up, years 10.6 11.5 9.3 Outcome (primary) Biochemical and local control MFS (also OS) Biochemical (Too few events for MFS and OS; main benefit for margin+) Adjuvant and early salvage not directly compared; may enjoy similar benefits? Node positive disease not evaluated
RTOG 9601 N= 760 Salvage RT Benefit for Overall Survival at 12 years: 76.3% bicalutamide vs 71.3% placebo Post hoc risk analysis suggests less benefit: Gleason <= 7 PSA < 0.7 negative margins Shipley WU N Engl J Med, 2017
Treatment of Hormone-Sensitive Disease
NCIC/PR7: Intermittent vs. Continuous Non-Metastatic Disease after RT IAD is noninferior to CAD with respect to OS Crook JM N Engl J Med, 2012
SWOG 9346: Intermittent vs. Continuous Metastatic Disease HR 1.10; 90% CI, 0.99-1.23 CI exceeded upper boundary for noninferiority = 1.20 Intermittent is NOT not inferior to Continous therapy in metastatic HSPC TRANSLATION: Intermittent is POTENTIALLY inferior (lower boundary of CI <1.00 is inconclusive) Hussain N Engl J Med 2013
SUMMARY Hormone Sensitive Prostate Cancer Intermittent versus Continuous NCIC/PR7 - non-metastatic NS difference SWOG 9346 metastatic HR 1.10 (intermittent potentially inferior) Intermittent reasonable option for patients with non-metastatic prostate cancer For patients with metastases, needs to be individualized
Prostate Cancer Clinical States HORMONE-SENSITIVE Diagnosis 161, 360 Clinically Localized Disease Biochemical Recurrence (PSA) Active Surveillance Intermitten t ADT Surgery Metastatic CASTRATION -RESISTANT Deaths From Disease 26, 730 NonMetastatic Docetaxel 2015 Radiation +/- ADT Continuous ADT 3 trials of Docetaxel in metastatic hormone-sensitive prostate cancer; 2 with OS benefit, suggestion of most benefit in high volume disease Metastatic First-Line Treatment Metastatic Post-Chemo Docetaxel 2004 Cabazitaxel 2010 Sipuleucel -T 2010 Abiraterone 2011 Abiraterone 2012 Enzalutamide 2012 Enzalutamide 2014 Alpharadin 2013 Olaparib 2016
Metastatic Hormone Sensitive PC: GETUG 15 Trial Design
GETUG- 15: Overall Survival= Negative Trial
LANDMARK STUDY Metastatic Hormone Sensitive PC: ECOG 3805 (CHAARTED) Sweeney C N Engl J Med, 2015
Metastatic Hormone Sensitive PC: ECOG 3805 (CHAARTED) Overall Survival Sweeney C N Engl J Med, 2015
Metastatic Hormone Sensitive PC: ECOG 3805 (CHAARTED) High vs Low Volume Disease Clinical benefit of Docetaxel x 6 cycles most pronounced in patients with high voume disease Sweeney C N Engl J Med, 2015
Hormone Sensitive Prostate Cancer (M0 and M1) STAMPEDE James ND, Lancet, 2015
Hormone Sensitive Prostate Cancer (M0 and M1) STAMPEDE
Treatment of Castration Resistant Metastatic Prostate Cancer
OS Benefit in Recent mcrpc Trials
LANDMARK STUDY Proof of Principle that the Androgen Receptor is relevant even in advanced castration resistant disease
Abiraterone Acetate Selective and Irreversible Inhibition of CYP17 Secondary Mineralicorticoid Syndrome Suppression of the ReninAngiotensin Pathway Modified from Ang, et al, British Journal of Cancer, 2009 Agent Trial Median Overall Survival Hazard Ratio Abiraterone/prednisone vs placebo/prednisone COU-301-AA: POST DOCETAXEL DeBono et al, NEJM 2011 3.7 months 14.8 vs.10.9 0.65 Abiraterone/prednisone vs placebo/prednisone COU-302-AA: PRE-DOCETAXEL Ryan et al, NEJM 2013 5.2 months 35.3 vs. 30.1 0.79
Abiraterone Acetate Adverse Events of Special Interest Ryan CJ N Engl J Med 2013
Enzalutamide A Second Generation AR Antagonist Enzalutamide: 1. Binds with higher affinity Enzalutamide 2. Impairs nuclear translocation 3. Prevents DNA binding Chen et al., Lancet Oncology, 2009 Enzalutamide vs Placebo Trial Median Overall Survival Hazard Ratio AFFIRM: POST DOCETAXEL (Scher et al, NEJM 2012) 4.8 months (18.4 vs. 13.6) 0.63 PREVAIL: PRE-DOCETAXEL (Beer et al, NEJM 2014) 2.2 months (32.4 vs. 30.2) 0.71
Enzalutamide Most common AE and Events of Interest The most common grade >= 3 AE was HTN (7% enzalutamide) The most common cardiac event was Afib (2% enzalutamide) One patient in each study group had a seizure Beer TM N Engl J Med, 2014
Seizure potential and the development of AR antagonists AR antagonist drug class causes convulsions in laboratory animals at high doses by an off-target mechanism of GABAA inhibition1 AR antagonist seizure risk increases with brain drug concentrations1 Seizures have been observed in clinical testing of next generation AR antagonists such as BMS-641988 and enzalutamide 2,3 1Foster WR et al., Prostate, 2011 D et al., Clin Cancer Res, 2011; 3Scher HI et al., Lancet, 2010. 2Rathkopf
AR Ligand Binding Domain Mutations Associated With AR Resistance N-terminal effector domain C-terminal ligand binding domain DNA binding domain Normal AR protein Hinge region AR v7 splice variant (Antonarakis et al., 2014) AR v567 splice variant (Thadani-Mulero et al, 2014.) AR point mutations* W742C (741): Bicalutamide H875Y (874): Flutamide F877L (876): Enzalutamide/ARN-509 T878A (877): Abiraterone Figure modified from Bambury R, Seminars in Urol Oncol. 2015 *Current (former) nomenclature per AR Gene Mutations Database
Phase I Study of Apalutamide: Patient Example of Acquired AR F876L Mutation m, mutation; WT, wild type. No patients had the AR F876L mutation at baseline (N=30) 3 of 29 evaluable patients developed the AR F876L mutation at progression using the Beaming digital PCR assay Joseph JD, et al. Cancer Discov. 2013;3:1020-1029.
Best PSA Responses According to AR-V7 Status Enzalutamide Abiraterone No patients with ARV7 had a significant response to AR therapy Antonarakis ES N Engl J Med 2014
Multi-Insitutional Genomic Profiling of Patients with mcrpc 49% 71.3% 12.7% 90% metastatic CRPC with actionable mutations Robinson Cell 2015
Mateo J, et al. NEJM, 2015 The results of the TOPARP-A trial suggest that a common subset of metastatic prostate cancers can be molecularly stratified for treatment
January 28th- 2016-FDA Grants Olaparib Breakthrough Designation in mcrpc Olaparib received an FDA breakthrough therapy designation as a treatment for patients with BRCA1/2 or ATM-mutated mcrpc in those who have received a prior taxane-based chemotherapy and at least either hormonal agent enzalutamide or abiraterone acetate.
Evolution of Chemotherapy in mcrpc 1985: No evidence for palliative benefit from chemotherapy. Chemotherapy recommended only for clinical trials. 1996: Mitoxantrone + prednisone vs prednisone alone establishes a palliative benefit for mitoxantrone in 30% of symptomatic patients. Studies are too small to detect a survival benefit. FDA approval. 2004: The larger TAX327 and SWOG 99-16 trials show a 3 month improvement in survival (16 19 months) for Docetaxel compared to Mitoxantrone. FDA approval.
TAX 327 Established Docetaxel as the First-Line Standard of Care for Castration-Resistant Prostate Cancer: Benefit Was Restricted to Every 3 Week Dosing 1.0 Docetaxel 3 wkly Probability of Surviving 0.9 Docetaxel wkly 0.8 Mitoxantrone 0.7 0.6 0.5 0.4 0.3 0.2 Docetaxel every 3 weeks: Docetaxel weekly: Mitoxantrone 0.1 0.0 0 6 Median survival (mos) 18.9 17.3 16.4 12 Months Hazard ratio 0.76 0.91 18 P-value 0.009 0.3 24 30 Tannock et al., NEJM, 351:1502, 2004
TROPIC: Phase III Study Cabazitaxel after Docetaxel in MCPRC De Bono J Lancet 2010
Cabazitaxel in mcrpc (TROPIC) Primary Endpoint: Overall Survival Granulocytopenia fever 7%: Consider prophylactic growth factor support in those at higher risk (multiple risk factors)
PROSELICA: non-inferiority study Cabazitaxel 25 mg/m2 (C25) vs 20 mg/m2 (C20) C20 N-598 C25 N=602 Grade 3-4 AE 39.7% 54.5% Grade 4 Neutropenia 21.3% 48.6% Neutropenic infection 2.2% 6.1% C20 is non-inferior for OS compared with C25 and C20 demonstrated an improved safety profile Modified from de Bono JS ASCO Annual Meeting 2016
OS Benefit in Recent mcrpc Trials
Sipuleucel-T: Mechanism of Action
Randomized Phase 3 IMPACT Trial (Immunotherapy Prostate Adenocarcinoma Treatment)
IMPACT Overall Survival Final Analysis (349 events)
Sipuleucel-T Questions While this was a breakthrough in terms of validating a new MOA and validating the principles of immunotherapy, the acceptance and adoption have been slow: Controversial MOA- does it really work the way we thought? Few PSA declines No measurable prolongation in TTP Other agents with more straightforward MOAs have been developed Cost Slide courtesy of PW Kantoff
Modified from Graff et al., ESMO 2016 Modified from Graff et al., Oncotarget 2016 Early evidence of anti-pd-1 activity in enzalutamide-resistant prostate cancer Responder Cycle 1 N=28 PSA (ng/ml) every 3-weeks and nadir Measurable Disease at Baseline Best Radiologic Response 1 April 2015 70.65 11.11 1.18 0.11 0.08 Yes (lymph) PR 2 October 2015 46.09 41.22 12.99 9.89 0.02 No n/a 3 January 2016 2502.75 1.26 0.07 0.01 <0.01 Yes (liver) PR 4 March 2016 82.43 17.34 0.3 0.01 No n/a 5 June 2016 250 88.69 5.1 0.43 0.18 Yes (liver) PR None of the responders have relapsed as of 10/2016.
OS Benefit in Recent mcrpc Trials
Radium- 223 Targets Bone Metastases
ALSYMPCA Phase III Study Design Parker C N Engl J Med 2013
ALSYMPCA TRIAL Radium - 223 in mcrpc Significantly improved OS by 3.6 mos Parker C N Engl J Med 2013 Significantly improved time to first SSE by 5 mos
ALSYMPCA Adverse Events of Interest Parker C N Engl J Med 2013
Prevention of skeletal-related events (SREs) in men with metastatic CRPC
Phase III Double- Blind Study of Denosumab vs Zolendronic Acid in mcrpc Fizazi K Lancet 2011
Conclusions Prevention of SREs Denosumab was superior to Zoledronic Acid in delaying SRE (18% risk reduction). The incidence of ONJ was higher in the Denosumab group but this was not statistically significant (2.3% vs. 1.3%; p=0.09). There was no benefit in terms of PSA, Disease progression, or overall survival. Bone protective agents zoledronic acid or denosumab are reasonable alternatives (NCCN guidelines)
FINAL THOUGHTS Screening and Prevention ACS, NCCN, AUA, USPSTF do NOT recommend universal PSA screening SELECT TRIAL: Vitamin E may increase risk PCPT (and REDUCE) trials: alpha reductase inhibitors have no effect on OS
FINAL THOUGHTS Treatment Localized Disease Primary ADT is NOT recommended 3 TRIALS comparing primary treatment: - SPCG-4: most benefit from RP if <65, intermediate risk PC - PIVOT: RP did not reduce all cause or PCSM - ProtecT: RP and RT reduce disease progression but PCSM is low regardless of assigned treatment arm Adjuvant and Salvage RT are both reasonable
FINAL THOUGHTS Treatment HSPC Intermittent ADT for non-metastatic disease after RT is reasonable (NCIC/PR7) Intermittent ADT for metastatic disease is potentially inferior to continuous ADT (SWOG 9346); personalize approach to patient Docetaxel is a standard of care for newly diagnosed metastatic HSPC assuming acceptable comorbidities; most benefit is in high volume disease (ECOG3805, STAMPEDE)
FINAL THOUGHTS Treatment mcrpc Abiraterone and Enzalutamide are approved both pre and post Docetaxel (COU-301, COU-302, PREVAIL, AFFIRM); it is as of yet unknown how best to sequence these agents AR is overexpressed in mcrpc; AR point mutations and ARV7 splice variants may act as predictive biomarkers for response to treatment Olaparib has activity in mcrpc patients with DNA mismatch repair deficiencies (TOPARP-A)