Management of advanced hormone-sensitive and castration-resistant prostate cancer Matthew D. Galsky, MD Director, GU Medical Oncology Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York, NY

Overview Early chemotherapy in patients with metastatic hormone-sensitive prostate cancer New generation “hormonal” therapies for castration-resistant disease Integration of immunotherapy and radiopharmaceuticals

New Drug Approvals in Prostate Cancer Galsky et al, CA: A Cancer Journal for Clinicians, 2012

Early chemotherapy in patients with metastatic hormone-naïve disease 4

Huggins: ADT for Prostate Cancer To put this problem into some historical context, ADT has been recognized as an effective treatment for metastatic prostate cancer since the seminal studies of Huggins and his colleagues in the 1940s. Dr. Huggins was awarded the Nobel Prize for Medicine for his observations that metastatic prostate cancer is dependent on androgen for growth, and that surgical or medical castration can induce significant and prolonged regressions of prostate cancer.

Docetaxel in Prostate Cancer The standard of care for CRPC changed from mitoxantrone/prednisone to docetaxel/prednisone based on SWOG 99-16 and TAX-327 studies SWOG 99-16 TAX-327 HR: 0.83, P=0.03 The standard of care for CRPC was recently changed from mitoxantrone-based chemotherapy to docetaxel-based chemotherapy based on the results of the TAX-327 and SWOG 99-16 trials.1,2 In the SWOG 99-16 trial, docetaxel/estramustine therapy improved median survival by 2 months compared to mitoxantrone/prednisone therapy. The graphs on the left highlights overall survival rates in both treatment arms. As you can see, docetaxel/estramustine resulted in fewer deaths than mitoxantrone/prednisone.1 In the TAX-327 trial, researchers found that docetaxel therapy led to improved survival and rates of response in terms of pain, PSA level, and quality of life compared to mitoxanthrone/prednisone therapy. The graph on the right demonstrates probability of overall survival among the three treatment arms. In this study, docetaxel (every 3 weeks) was superior to weekly docetaxel or mitoxantrone/prednisone therapy.2 References: Petrylack DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxanthrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-1520. Tannock TF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512. Petrylak N Engl J Med. 2004 Tannock, N Engl J Med. 2004

Early Chemotherapy +ADT for metastatic prostate cancer? Attack de-novo testosterone independent clones early - allow ADT to keep PrCa in remission longer Some patients at the time of progression are too frail for chemo. Con ADT will take cells out of cycle and be less responsive to cytotoxics Some patients respond for a long time and never need chemotherapy Androgen Deprivation Therapy Regression Re-emergence Sweeney et al, ASCO, 2014

E3805 – CHAARTED Treatment Stratification Extent of Mets High vs Low Age ≥70 vs < 70yo ECOG PS - 0-1 vs 2 CAB> 30 days -Yes vs No SRE Prevention Prior Adjuvant ADT ≤12 vs > 12 months Evaluate every 3 weeks while receiving docetaxel and at week 24 then every 12 weeks ARM A: ADT + Docetaxel 75mg/m2 every 21 days for maximum 6 cycles RANDOMIZe Follow for time to progression and overall survival Chemotherapy at investigator’s discretion at progression ARM B: ADT (androgen deprivation therapy alone) Evaluate every 12 weeks ADT allowed up to 120 days prior to randomization. Intermittent ADT dosing was not allowed Standard dexamethasone premedication but no daily prednisone High volume: visceral metastases and/or 4 or more bone metastases (at least 1 beyond pelvis and vertebral column)

Primary endpoint: Overall survival HR=0.61 (0.47-0.80) p=0.0003 Median OS: ADT + D: 57.6 months ADT alone: 44.0 months Sweeney et al, ASCO, 2014

OS by extent of metastatic disease at start of ADT High volume Low volume p=0.0006 HR=0.60 (0.45-0.81) Median OS: ADT + D: 49.2 months ADT alone: 32.2 months p=0.1398 HR=0.63 (0.34-1.17) Median OS: ADT + D: Not reached ADT alone: Not reached In patients with high volume metastatic disease, there is a 17 month improvement in median overall survival from 32.2 months to 49.2 months Sweeney et al, ASCO, 2014

Clinical States of Prostate Cancer Clinically localized “Rising PSA” state Non-metastatic, hormone- sensitive Non-metastatic CRPC Metastatic, hormone-sensitive Metastatic CRPC This flow chart shows the clinical states of prostate cancer. Progression from clinically localized disease to metastatic AIPC generally spans 10-15 years or more. Death from prostate cancer Death from other causes 10-15 years + 11

New generation of “hormonal therapies” for castration-resistant disease 12

What is castration-resistance? CRPC is NOT Hormone Refractory Cancer, 500 ng/mL Testosterone but is frequently Hormone Ultra-Sensitive PSA 50 ng/mL Castration Therapy Castration Resistance

T Androgen Deprivation Therapy CRPC selective pressure adaptation ABERRANT MODIFICATION GF, cytokines Src Sumo AC P COFACTOR PERTURBATION CoAct gain CoR loss/dismissal CoACT MUTATION gain of function AR AR DEREGULATION amplification overexpression INTRACRINE ANDROGEN SYNTHESIS T ALTERN. SPLICING RESTORED AR ACTIVITY (rising PSA) CRPC

T Androgen Deprivation Therapy CRPC selective pressure adaptation ABERRANT MODIFICATION GF, cytokines Src Sumo AC P COFACTOR PERTURBATION CoAct gain CoR loss/dismissal CoACT MUTATION gain of function AR AR DEREGULATION amplification overexpression INTRACRINE ANDROGEN SYNTHESIS T ALTERN. SPLICING RESTORED AR ACTIVITY (rising PSA) CRPC

Enzalutamide T T Enzalutamide AR Tumor AR Death Oral drug rationally designed to target AR signaling, impacting multiple steps in AR signaling pathway. No demonstrated agonist effects in pre-clinical models. T T Enzalutamide Inhibits Binding of Androgens to AR 1 AR Cell cytoplasm Inhibits Nuclear Translocation of AR 2 Cell nucleus Tumor Death AR Inhibits Association Of AR with DNA 3 Tran et al. Science 2009;324:787–90. Charles Sawyers & Michael Jung

T Androgen Deprivation Therapy CRPC selective pressure adaptation ABERRANT MODIFICATION GF, cytokines Src Sumo AC P COFACTOR PERTURBATION CoAct gain CoR loss/dismissal CoACT MUTATION gain of function AR AR DEREGULATION amplification overexpression INTRACRINE ANDROGEN SYNTHESIS T ALTERN. SPLICING RESTORED AR ACTIVITY (rising PSA) CRPC

Abiraterone (CYP-17 Inhibitor) Reduce adrenal androgen synthesis by inhibition of 17α-hydroxylase and C17,20-lyase. These enzymes are needed to produce the precursors of the sex steroids in both the adrenal cortex and testicles…. and in prostate cancer cells…… Abiraterone is a potent and selective CYP17 inhibitor unlike keto which is a less potent and competitive inhibitor of several CYP enzymes. Cytochrome p17 is a microsomal enzyme that catalyzes two independently regulates steroid reactions key to androgen and estrogen biosynthesis. I should mention that there is also evidence that CYP-17 is expressed in the bone metastases based on an abstract at this years ASCO. Attard, JCO, 2008

Expected Toxicities of CYP17 Inhibition ACTH increases DOC and Corticosterone increase Expected side effect profile  mineralocorticoid excess Hypokalemia Hypertension Fluid overload The side effects of CYP17 inhibition can be predicted based on what happens in patients with congenital CYP17 deficiency. CYP loss interupts the negative feedback control of ACTH – this results in an increase in DOC and corticosterone and the resulting side effects of mineralocorticoid excess – hypokalemia, hypertension, and fluid overload. Rise in ACTH blunted with co-administration of steroids Attard, JCO, 2008

Abiraterone and Enzalutamide: 07/12/09 Abiraterone and Enzalutamide: Four Positive Studies! mCRPC Pre-chemotherapy mCRPC 1st Line Chemotherapy mCRPC Post-chemotherapy COU-AA-302 COU-AA-301 PREVAIL AFFIRM Co-Primary Endpoints: OS, rPFS Primary Endpoint: OS

PREVAIL: Radiographic Progression-Free Survival Median rPFS: Enzalutamide, not reached Placebo, 3.9 months Beer T, et al. J Clin Oncol. 2014;32(suppl 4): Abstract LBA 1.

COU-AA-302: Abiraterone Acetate ~Doubles rPFS in Pre-Chemo mCRPC 100 Abiraterone (median, mos): 16.5 Prednisone (median, mos): 8.3 HR (95% CI): 0.53 (0.45-0.62) p Value: < 0.0001 80 60 Subjects Without Progression or Death (%) 40 20 Abiraterone Prednisone 3 6 9 12 15 18 21 24 27 30 33 36 Months From Randomization Abiraterone Prednisone 546 542 485 406 389 244 311 176 240 133 195 99 157 78 131 62 117 45 66 20 20 7 4 Rathkopf GU ASCO 2013

Time to PSA progression COU-302 vs PREVAIL COU-302 PREVAIL Abiraterone/ Prednisone Enzalutamide Placebo Prednisone Use? Y N Visceral Disease Grade 3/4 AE 48% 42% 43% 37% PSA RR 62% 24% 78% 3% rPFS 16.5 mo 8.3 mo 15-18 mo 3.9 mo OS 34.7 mo 30.3 mo 32.4 mo 30.2 mo Time to chemo 25 mo 16.8 mo 28 mo 10.8 mo Time to PSA progression 11.2 mo 5.6 mo 11.1 mo 2.8 mo Zhang Expert Opin Pharmacother 2015

Substantial (but incomplete) cross-resistance between these therapies Author Year N Median Duration PSA Decline > 50% ENZA ABI Loriot 2013 38 3 mo 3% Noonan 30 3.2 mo ABI ENZA Schrader 35 4.9 mo 29% Badrising 2014 61 21% Bianchini 39 2.9 mo 23% Schmid 2.8 mo 10% Brasso 137 18%

Phase III Enzalutamide +/- Abiraterone Acetate + Prednisone in Treating Patients With Metastatic CRPC R A N D O M I Z E 2:1 Patients with mCRPC with no prior docetaxel Enzalutamide 160 mg daily days 1-28 Endpoints Primary: OS Key Secondary: PFS and rPFS PSA response Toxicity Enzalutamide 160 mg daily Abiraterone Acetate 1000 mg daily Prednisone 5 mg BID Enrollment Goal N = 1224 PI: Michael Morris, MD Available at http://www.clinicaltrials.gov/NCT01949337

Can patients be identified that will not respond to abiraterone and enzalutamide? 26

T Androgen Deprivation Therapy CRPC selective pressure adaptation ABERRANT MODIFICATION GF, cytokines Src Sumo AC P COFACTOR PERTURBATION CoAct gain CoR loss/dismissal CoACT MUTATION gain of function AR AR DEREGULATION amplification overexpression INTRACRINE ANDROGEN SYNTHESIS T ALTERN. SPLICING RESTORED AR ACTIVITY (rising PSA) CRPC

Androgen Receptor Splice Variants Nelson, NEJM, 2014

ARV7 is associated with lack of response to enzalutamide and abiraterone Antonarakis et al, NEJM, 2014

Galeterone Decreases AR and AR-V7 LuCaP136 Castration Resistant Xenograft µM Galeterone (72 hr) 1 2.5 5 AR AR-V7 b-Actin –110 kDa –80 kDa –45 kDa Galeterone Treatment Initiated CWR22rv1 Cells CWR22rv1 cells express wild type AR and AR-V7 Castration (Cx) Cx + Galeterone 250 mg/kg QD, PO 5x/wk Taplin et al, 26th EORTC-NCI-AACR Symposium

ARMOR2: Galeterone Activity in Patients with AR C-terminal Loss Time to PSA Progression (PCWG2): Median 7.3 months (95% CI 2.8–NE) M0 and M1 Treatment Naïve Arms * Maximal PSA, % Exposure (n=7) Time on treatment:155 to >334 days (ongoing) Four patients continued into optional extension phase Taplin et al, 26th EORTC-NCI-AACR Symposium

ARMOR3-SV Trial Schematic: Phase 3 Trial Secondary Endpoints Overall survival Skeletal related events Time to cytotoxic therapy Primary Endpoint Radiographic progression free survival Key Inclusion Criteria M1 disease Progressive disease on androgen deprivation therapy based on PCWG2 Detectable AR-V7 from CTCs ECOG 0 or 1 Key Exclusion Criteria Prior treatment with second generation antiandrogens (abiraterone, enzalutamide) Prior treatment with chemotherapy for CRPC Galeterone 2550 mg/day Randomize Enzalutamide 160 mg/day Other Endpoints Safety PSA50 Time to progression and ECOG deterioration Best overall response by RECIST 1.1 CTC characterization Pharmacokinetics Quality of life Taplin et al, 26th EORTC-NCI-AACR Symposium

The role of immunotherapy in metastatic CRPC? 33

Sipuleucel-T: Autologous APCs Cultured with Antigen Fusion Protein Recombinant Prostatic Acid Phosphatase (PAP) fusion antigen combines with resting antigen presenting cell (APC) APC takes up the antigen Antigen is processed and presented on surface of the APC Fully activated, the APC is now sipuleucel-T Inactive T-cell INFUSE PATIENT Active T-cell T-cells proliferate and attack cancer cells sipuleucel-T activates T-cells in the body

Sipuleucel-T Survival Benefit Sipuleucel-T was approved based on HR 0.775 (~4 month OS benefit) Survival curves separate after 6 months Treatment is done in 5 weeks Well tolerated Kantoff NEJM 2010

Survival Benefit of Sip-T is Greater When PSA is Lower 7/5/2018 Survival Benefit of Sip-T is Greater When PSA is Lower IMPACT: Overall Survival by Baseline PSA Baseline PSA ≤22.1 >22.1–50.1 >50.1–134.1 >134.1 n 128 Median OS, months -Sipuleucel-T 41.3 27.1 20.4 18.4 -Control 28.3 20.1 15.0 15.6 -Difference 13.0 7.1 5.4 2.8 HR 0.51 (0.31, .85) 0.74 (0.47, 1.17) 0.81 (0.52, 1.24) 0.84 (0.55, 1.29) Baseline PSA (ng/mL) 41.3 28.3 13.0 27.1 20.1 7.1 20.4 15.0 5.4 18.4 15.6 2.8 HR (95% CI) 0.51 (0.31, 0.85) 0.74 (0.47, 1.17) 0.81 (0.52, 1.24) 0.84 (0.55, 1.29) Schellhammer Urology 2013

Radium-223 Is For Symptomatic Patients With Bone Mets 37

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 Ca Sr Ba Ra

Radium-223 Targets Bone Metastases Range of alpha-particle Radium-223 Bone surface Alpha-particles induce double-strand DNA breaks in adjacent tumour cells Short penetration of alpha emitters (2-10 cell diameters) = highly localized tumour cell killing and minimal damage to surrounding normal tissue

ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design TREATMENT 6 injections at 4-week intervals Radium-223 (50 kBq/kg) + Best standard of care Placebo (saline) + Best standard of care R A N D OM I S E D 2:1 N = 921 PATIENTS Confirmed symptomatic CRPC ≥ 2 bone metastases No known visceral metastases Post-docetaxel or unfit for docetaxel Total ALP: < 220 U/L vs ≥ 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No STRATIFICATION

ALSYMPCA Updated Analysis Overall Survival 100 HR = 0.695 95% CI, 0.581, 0.832 P = 0.00007 90 80 70 60 % 50 Radium-223, n = 614 Median OS: 14.9 months 40 30 20 Placebo, n = 307 Median OS: 11.3 months 10 Month 3 6 9 12 15 18 21 24 27 30 33 36 39 Radium-223 614 578 504 369 274 178 105 60 41 7 1 Placebo 307 288 228 157 103 67 14 4 2

Standard Androgen Deprivation Therapy Denosumab, Zoledronic Acid Treatment Landscape Standard Androgen Deprivation Therapy Surgery / Radiation Denosumab, Zoledronic Acid Radium-223 Enzalutamide Abiraterone Local Therapy Androgen Deprivation Death Interventional therapy Surgery, Radiation, Cryosurgery, Brachytherapy in curative setting, not competition First-line hormonal therapy LHRH Agents (Lupron, Zoladex, Firmagon) given to metastatic patients to control PSA, disease progression. Most likely to be continued with Abiraterone however a successful head to head trial or early stage combination trial would have profound positive impact on uptake Antiandrogens Casodex given with LHRH in an effort at combined androgen blockade or as a second line agent. Clinical trial efficacy is mixed but embraced by HCPs. Antiandrogen withdrawal can actually lower PSA. Provenge Immunotherapy launched in Q2 2010. Labeled for mild/asymptomatic mCRPC. Should be direct competitor to 302 indication although patients could receive both drugs. Prostvac-VF is similar agent in development Taxotere Chemotherapy is standard of care with prednisone. Patent likely to expire in 2011. Sandwiched between 301 and 302 indications it is a threat. Jevtana Follow-on taxane from sanofi-aventis launched in Q3 2010 in post Taxotere failures. Use could delay onset of abiraterone usage in 301 setting. Sipuleucel-T Docetaxel Cabazitaxel 42

The next few years….. More agents some will be “me too” drugs? Increased understanding of the biology of CRPC Earlier use of therapies Adjuvant, neoadjuvant, rising PSA, non-mets CRPC More molecular diagnostics and personalization of prostate cancer subtypes True “hormone refractory” disease