Integrating Current & Novel Treatment Strategies for the Management of CRPC Charles J Ryan, MD Thomas Perkins Distinguished Professor of Medicine and Urology Helen Diller Family Comprehensive Cancer Center University of California, San Francisco 1 UC SF Progress in Metastatic Prostate Cancer FDA Approvals in Castration-Resistant Prostate Cancer Survival Docetaxel Radium-223 Enzalutamide Cabazitaxel Abiraterone Sipuleucel-T 1992 1996 2000 2004 2008 2012 Strontium-89 Samarium-153 Zoledronic acid Denosumab Mitoxantrone Palliation 1
Available Treatment Agents for Advanced Prostate Cancer Androgen deprivation therapy (ADT) Death Local therapy Therapies after ADT Hormone sensitive mcrpc asymptomatic (failed ADT) mcrpc mildly symptomatic mcrpc symptomatic mcrpc postdocetaxel ADT Abiraterone Abiraterone ADT + Docetaxel in highvolume disease? Enzalutamide Docetaxel Radium 223 Enzalutamide Cabazitaxel Sipuleucel-T supportive care (eg denosumab/bisphosphonates) 1. How do we define Castration Resistant Prostate Cancer? 500 ng/ml 50 ng/ ml PSA Testosterone Progression of Disease despite a suppressed (castrate) testosterone level (<50ng/dL) Castration Therapy Castration Resistance 5 2. What makes prostate cancer lethal and how do we assess prognosis in patients? 500 Testosterone ng/ml 50 ng/ PSA ml + = Lethal Prostate cancer Castration Therapy Castration Resistance 5 2
What s the Prognosis? CRPC Chemo-naïve Prognostic Nomogram Wide Range. Halabi et al JCO 2014 5 Perisistent AR Signaling Pathway is the Pivotal Target of CRPC treatment Depiction of mechanisms of resistance to androgen deprivation therapy: AR amplification increased intratumoral androgen synthesis hypersensitivity of AR mutations of AR alternative splicing of AR to constitutively active splice variants. Anantharaman A, Friedlander TW. Targeting the androgen receptor in metastatic castrate-resistant prostate cancer: A review. Urol Oncol. 2015 Dec 16. 3
Mechanism #1 Immunotherapy UC SF Provenge: Background APC8015 Sip-T Antigen Loading Antigen Processing 20 Precursor APC Antigen-loaded precursor APC Maturing antigenloaded APC Infuse patient PSA (ng/ml) s 15 10 5 T cells attack tumor cells In vivo T cell activation 0-10 0 10 20 30 Week Small EJ et al., J Clin Oncol 18: 3894, 2000 4
Provenge: (second) Pivotal Trial Results Phase 3 design allowed for crossover from placebo to vaccine Adverse Events Adverse event All Grades (%) PROVENGE (n=338) Grades 3 5 (%) All Grades (%) Control (n=168) Grades 3 5 (%) Chills 54.1 1.2 12.5 0 Fever (pyrexia) 29.3 0.3 13.7 1.8 Headache 16.0 0.3 4.8 0 Influenza like illness 9.8 0 3.6 0 Myalgia 9.8 0.6 4.8 0 Hypertension 7.4 0.6 3.0 0 Hyperhidrosis 5.3 0 0.6 0 Groin pain 5.0 0 2.4 0 Primary endpoint: Overall survival 1,2 Secondary endpoint: Objective disease progression 2 Control was nonactivated, autologous, peripheral blood mononuclear cells. Kantoff PW et al. N Engl J Med. 2010;363:411-422. UC SF Provenge: (second) Pivotal Trial Results: Peak effect at 3 years Kantoff PW et al. N Engl J Med. 2010;363:411-422. UC SF 5
Mechanism #2 Targeting Persistent AR signaling UC SF The Human Endocrine System Drives Prostate Cancer Growth Hypothalamus (Brain) Estrogen LHRH agonists (Lupron, Zoladex) LHRH Pituitary Gland orchiectomy FSH, LH Testicles Testosterone Adrenal gland Abiraterone Abiraterone DHT PROSTATE CANCER CELLS Antiandrogens: Casodex Flutamide Nilutamide, Enzalutamide, Apalutamide 6
- 5-10 - 15-20 - 25 0-5 - 10-15 - 20-25 5 0-5 - 10-15 - 20 5 0-5 - 10-15 - 20 0-5 - 10-15 - 20-25 11/14/2016 Model of AR Amplification as Mechanism of Resistance to Androgen Deprivation Therapy Chen et al., 2004 Nature Medicine AR targeting: Abiraterone Intracrine Androgens Enzalutamide AR amplification - - - - 0 P<0.0001 P=0.0091 BP CP METS BP CP METS 3BHSD1 3BHSD2 P=0.0005 BP CP METS CYP17A P=0.0026 P<0.0001 BP CP METS BP CP METS AKR1C3 17BHSD3-10 - - P=0.0050 BP CP METS BP CP METS SRD5A1 SRD5A2 P=0.0031 P=0.0004 P=0.0013 BP CP METS BP CP METS UGT2B15 UGT2B17 1. Transcripts encoding steroidogenic enzymes are detected within tumor 2. Tumor androgens in CRPC metastases from anorchid patients exceed levels in prostate cancer tissues from eugonadal subjects 3. These may be particularly relevant for tumors with overexpressed AR CRPC samples have robust AR expression Mohler et al Montgomery RB et alcancer Res. 2008 Jun 1;68(11):4447 54 7
Prostate Cancer can make its own androgens 0 P<0.0001 P=0.0091-5 - 10-15 - 20-25 0-5 - 10-15 - 20-25 BP CP METS BP CP METS 3BHSD1 3BHSD2 P=0.0005 BP CP METS CYP17A 5 0 P=0.0026 P<0.0001-5 - 10-15 - 20 BP CP METS BP CP METS AKR1C3 17BHSD3 5 0 P=0.0050 P=0.0004-5 - 10-15 - 20 BP CP METS BP CP METS SRD5A1 SRD5A2 Montgomery RB et alcancer Res. 2008 Jun 1;68(11):4447 54 0 P=0.0013-5 P=0.0031-10 - 15-20 - 25 BP CP METS BP CP METS UGT2B15 UGT2B17 Testosterone Levels Within Metastases From the Castrate Men Exceeded Serum Levels The level of androgen in the tumor tissue Serum testosterone castration stage cannot completely eradicate androgens in PC environment There are enough androgens within the tumor tissue to activate AR tar DHT, dihydrotestosterone; T, testosterone Mostaghel et al. Urol Oncol 2009; 27(3): 251 257 8
ACTH x 5 Hypokalemia Hypertension Fluid overload Renin suppression Negative feedback Abiraterone Pregnenolone Deoxycorticosterone x 20 Corticosterone x 60 Aldosterone x 2 17α-hydroxpregnenolone 11-deoxycortisol x 5 Cortisol x 2 DHEA-S < 15 μg/dl LLQ Androstenedione Testosterone 1-2 ng/dl Enzalutamide (Xtandi) Oral drug rationally designed to target AR signaling, impacting multiple steps in AR signaling pathway. No demonstrated agonist effects in pre clinical models. 1 2 T Inhibits Binding of Androgens to AR Cell cytoplasm Inhibits Nuclear Translocation of AR T Enzalutamide AR Cell nucleus AR 3 Inhibits Association Of AR with DNA Tran et al. Science 2009;324:787 90. 9
Hormonally Driven Resistance Pre Receptor (Ligand) and Receptor Events Pre Receptor Events: Receptor events: AR Amplification and Mutation AR Splice Variants Adrenal Androgen Production And Polymorphisms Intracrine Androgen Production Ryan, Tindall Journal of Clinical Oncology 2011 Two very active agents Abiraterone/PredvsPrednisone Enzalutamide Vs Placebo Radiographic Progression-Free Survival (%) 100 90 80 70 60 50 40 30 20 10 0 Enzalutamide Placebo Hazard Ratio: 0.186 (95% CI: 0.15, 0.23) P<0.0001 0 3 6 9 12 15 18 21 Radiographic Progression-Free Survival (Months) 100 90 80 Hazard Ratio: 0.706 (95% CI: 0.60,0.84) P<0.0001 Survival (%) 70 60 50 40 30 20 10 Enzalutamide Patients still alive at data cut off Placebo Enzalutamide: 72%; Placebo: 63% 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Duration of Overall Survival (Months) Patients at Risk Ryan et al NEJM 2013, Lancet Onc 201 Enzalutamide 872 863 850 Beer 824 et 797 al NEJM 745 2014 566 395 244 128 33 2 0 Placebo 845 835 781 744 701 644 484 328 213 102 27 2 0 10
Progress for Most ( 69% of patients respond to abiraterone) Abiraterone + Prednisone Placebo + Prednisone Maximal Decline From Baseline (%) 100 75 50 25 0-25 -50-75 -100 29% of patients on the prednisone control arm had a decline in PSA by 50% 69% of patients on the abiraterone arm had a decline in PSA by 50% IA3 data. A negative percent indicates a decline in PSA. A positive percent indicates that the subject never has a decline in PSA. 2 1 Time to All Landmarks Favored Abiraterone for the population as a whole Secondary Endpoints Baseline p < 0.0001 PSA Progression p < 0.0001 p = 0.001 p = 0.0053 Pain Tumor/Bone Progression ECOG PS Decline Death Chemotherapy p < 0.0001 p = 0.0097 Primary Endpoints: rpfs and OS 24 48 months Adapted from Halabi S, J Clin Oncol 2009;27: 2766-2771. ECOG PS = Eastern Cooperative Oncology Group Performance Status. Ryan et al Proc ASCO 2012 11
But not a home run for all A patient who does not respond to abiraterone has rpfs and OS no different from Tax 327 data of a decade ago. Ryan et al Proc ASCO 2013 Who Does Best with Abiraterone/Enzalutamide? Kaplan Meier estimates of OS and HRs (relative to the good prognosis category) were determined Baseline risk factor p Value Hazard ratio BPI (2-3 vs 0-1) < 0.0001 1.71 (1.34-2.17) LDH ( > ULN [234 IU/L] vs ULN) < 0.0001 2.03 (1.51-2.74) ALP ( > ULN [131 IU/L] vs ULN) 0.0004 1.60 (1.23-2.08) Bone metastases ( 10 vs < 10) < 0.0001 1.92 (1.49-2.47) 12
Sequen cing: Retrospective Experience Abiraterone after enzalutamide Very Modest response Study N Sequence (order drugs administered) Ileana 2012 24 Docetaxel Enzalutamide Abiraterone Noonan 2013 30 Docetaxel Enzalutamide Abiraterone Loriot 2013 38 Docetaxel Enzalutamide Abiraterone PSA Response Enzalutamide Therapy ( 50%) PSA Response ( 50%) Response to Abiraterone Therapy Median PFS Median OS 13% 2.4 months 60% 3% 15.4 weeks 50.1 weeks 8% 2.7 months 7.2 months Earlier Intervention for More Survival Benefits with 11.8 mo of OS Extended 2016 EAU COU- AA-302 stratified analysis Earlier Stage of Chemotherapynaïve mcrpc subjects: [BPI] Short Form score 0-1 [PSA] < 80 ng/ml [GS] Gleason score < 8 placebo+pred nison 41.8m HR=0.61 (95% CI: 0.43-0.87) p=0.0055 Treatment with AA + P significantly prolonged OS to 53.6 months abiraterone + prednisone (n=124) --- + prednisone (n=140) COU-AA-302randomized,double-blind,placebo-controlledphaseIIIclinicalstudy.Themediantreatmentperiod abiraterone+prednisone20.4m,placebo+prednisone11.2m(hr0.41,95%ci0.31-0.54,p<0.0001) Miller K, et al. Poster (#775) presented at the 31st Annual EAU Congress, 11 15 March 2016, Munich, Germany 26 13
Primary Resistance Ryan Proc GU ASCO 2013 30% = Primary Resistance (?%) Resistance with Phenotypic Change: e.g. Neuro-endocrine Enzalutamide Or Abiraterone Response 60+% = Acquired Resistance: ASI= Androgen Synthesis Inhibitor ART = AR Targeted Therapy CRPC Death Non-PC Cause AR V7: AR SPLICE VARIANT half AR Activated without Binding Androgen CBP CRPC contains variants which lack LBD No current therapies can inhibit because they work through LBD NTD DBD Hinge LBD Antonarakis ES. 2014 ASCO Annual Meeting. Abstract 5001. 14
AR Splice Variants (AR Vs) 8753 nts 69 nts 4155 nts AR: Xq11-12 1 1b 2 CE4 3 CE1 CE2 CE5 CE3 4 5 6 7 8 9 66937320 66942669 66766604 66788864 66937464 66942826 66948516 66763874 66863098 66900562 66905852 66909400 66913412 66931244 66788683 66915918 66941675 66900845 66905968 66912029 66943528 66863249 66914515 66931531 66941805 66944119 AR-Vs AR-V1 AR-V2 AR-V3 AR-V4 AR-V5 AR-V6 AR-V7 AR-V8 AR-V9 AR-V10 AR-V11 AR-V12 AR-V13 AR-V14 Alternative names AR4 AR1/2/2b AR1/2/3/2b AR3 AR v567es Transcriptional activity Conditional Unknown Constitutive Constitutive Unknown Unknown Constitutive Unknown Conditional Unknown Unknown Constitutive Inactive Unknown Transcripts 1 2 3 CE1 1 2 3 3 CE1 1 2 CE4 3 CE1 1 2 3 CE4 3 CE1 1 2 3 CE2 1 2 3 CE2 1 2 3 CE3 1 2 3 1 2 3 CE5 3 4 8 1 2 9 3 4 5 6 1 2 9 1 2 7 3 4 5 6 9 Proteins MTLGAVVVSERILRVFGVSEWOP stop MTLGAVVVSERILRVFGVSEWOP stop RAAEGFFRMNKLKESSDTNPKPYCMAAPMGLTENNRNRKKSYRETNLKAVSWPLNHT stop MTLGGFFRMNKLKESSDTNPKPYCMAAPMGLTENNRNRKKSYRETNLKAVSWPLNHT stop MTLGD stop MTLGAGSRVS stop MTLGEKFRVGNCKHLKMTRP stop MTLGGFDNLCELSS stop MTLGDNLPEQAAFWRHLHIFWDHVVKK stop 1 2 3 MTPSSGTNSVFLPHRDVVRTGCRSNSGYHSCSCEYHDYCFL stop 1 2 3 MTLGGKILFFLFLLLPLSPFSLIF stop KALPDCERAASVHF stop LFSINHT stop SVQPITPDAMYL stop Liu LL et al, Oncogene 2013 ARV7 More abundant than others: Compatible with detection in clinical samples Constitutively active: Cannot be inhibited by LBD targeting drugs Produces translated protein product: Not affected by nonsense mediated mrna decay Expression increased (~20 fold) in CRPC Prevalence of AR V7 in CRPC (n=62) Pre Enza, Pre Abi : 11.6% Post Enza only : 25.0% Post Abi only : 51.2% Post Enza and Post Abi : 66.7% 15
AR V7 and Resistance to Enzalutamide and Abiraterone in CRPC PSA Responses According to AR V7 Status Enzalutamide Treated Patients Best PSA Response, % change 100 50 0 50 * * * AR V7 positive AR V7 negative Abiraterone Treated Patients Best PSA Response, % change 100 50 0 50 * * ** AR V7 positive AR V7 negative 100 The dotted line shows the threshold for defining a PSA response ( 50% reduction in PSA level from baseline). *Increase seen of > 100% in best PSA response. Pa ents in the enzalutamide cohort who previously received abiraterone and patients in the abiraterone cohort who previously received enzalutamide. 100 Antonarakis ES, et al. N Engl J Med. 2014;371:1028 38. Conversions of ARV-7 Nakazawa et al Ann Oncol 2015 16
ARV7 ratio to flar: ARV7 is a function of AR amplfication Antonarakis NEJM 2014 Combination Phase III: Alliance: A031201 PI Michael Morris (accrued) Arm A: Enzalutamide Stratification factor: prior chemo Arm B: Enzalutamide Abiraterone Prednisone Total of 616 deaths, log rank statistic 90% power (one sided type I error rate of 0.025) to detect HR of 0.77 in favor of arm B 17
Mechanism #3 Targeting Bone Metastasis UC SF Radium-223 Targets Bone Metastases Range of alpha-particle Radium-223 Bone surface Alpha-particles induce double-strand DNA breaks in adjacent tumour cells 1 Short penetration of alpha emitters (2-10 cell diameters) = highly localised tumour cell killing and minimal damage to surrounding normal tissue 1. Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007:103. 18
ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design PATIENTS Confirmed symptomatic CRPC 2 bone metastases No known visceral metastases Post docetaxel or unfit for docetaxel STRATIFICATION Total ALP: < 220 U/L vs 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No R A N D O M I S E D 2:1 N = 922 TREATMENT 6 injections at 4-week intervals Radium-223 (50 kbq/kg) + Best standard of care Placebo (saline) + Best standard of care Planned follow-up is 3 years Clinicaltrials.gov identifier: NCT00699751. ALSYMPCA Overall Survival 100 90 80 HR 0.695; 95% CI, 0.552-0.875 P = 0.00185 % 70 60 50 40 30 20 10 0 Placebo, n = 268 Median OS: 11.2 months Radium 223, n = 541 Median OS: 14.0 months 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 19
Chemo refusers? Frailer patients? Post chemo In combination How to use radium? Mechanism #4 Targeting Variant Histologies UC SF 20
Treatment Mediated Selection Pressure: Neuro Endocrine Prostate Cancer as an example of phenotypic change AR directed therapy eliminates Adenocarcinoma AR Driven Adenocarcinoma Neuro endocrine/small cell predominant mcrpc Tissue Collection: West Coast Dream Team Approach 21
Histology of 124 Evaluable Biopsies<br />74 % were pure with a single histologic subtype (**isolated by LCM)<br />Remainder (26%) were comprised of mixed populations Presented By Eric Small at 2015 ASCO Annual Meeting Overall survival as function of biopsy pathology<br />Grouping IAC and SCNC Presented By Eric Small at 2015 ASCO Annual Meeting 22
Need to Reconcile clinical vs histological vs genomic Clinically Anaplastic Histologically Small Cell Genomic Target Present? But the holy grail is the liquid biopsy Scher et al Proc ASCO GU 2016 23
Harnessing Multi platform informatics to discover NEXT Ideal: A marker that melds Predictive and prognostic Prognostic how sick is patient? Predictive Will drug work? LDH AlkPhos Opiates y/n? Visceral Disease Does Prognostic trump Predictive? If a predictive pattern is identified in a patient will they still be able to receive the intervention? 24
Mechanism #5 Targeting DNA repair UC SF BRCA and prostate cancer Germline BRCA 1,2 are rare in prostate cancer present in 0.33 5% HOWEVER Homologous DNA repair defects (HR) are common in prostate cancer Germline and somatic inactivating mutations in HR DNA repair genes collectively occur in up to 20% 25% of prostate cancers CHEK2, BRIP1/FANCJ, SBS1, BRCA1 and ATM 25
Genomic Aberrations in DNA Repair in Patients with Metastatic, Castration Resistant Prostate Cancer. Mateo J et al. N Engl J Med 2015;373:1697 1708. Antitumor Activity of Olaparib and Association with Defects in DNA Repair Genes, According to Biomarker Status. Mateo J et al. N Engl J Med 2015;373:1697 1708. 26
PARP inhibitors in development Source: NIH Clinical Trials registry. www.clinicaltrials.gov. See more at: http://www.onclive.com/publications/oncologylive/2015/june 2015/parp inhibitors move into the limelight#sthash.x2kqz6ic.dpuf Carboplatin also targets defective DNA repair Platinum based chemotherapy active Underutilized. May double cover neuroendocrine and HRD tumors Generic, well tolerated Need trials! 54 27
Prior studies of platinum based therapy Hagel S et al, Ann Oncol 2016 Do we know how to select patients?? Mateo et al, NEJM 2015 Lord and Ashworth, Nat Rev Cancer 2016 28
Integrating Biology into CRPC Management AR signaling is the key to most CRPC Variant histologies also may be implicated. DNA Repair defects are a new Tumor interrogation imperative to future therapy development 29