Novel treatment for castration-resistant prostate cancer

Novel treatment for castration-resistant prostate cancer Cora N. Sternberg, MD, FACP Chair, Department of Medical Oncology San Camillo and Forlanini Hospitals Rome, Italy

Treatment options for patients with CRPC Zoledronic Acid 1 Sipuleucel-T 3 Docetaxel 2 Cabazitaxel 4 Denosumab 5 Abiraterone 6 22 24................. 21 211 The near future MDV31 7 Alpharadin 8 1 Saad et al. J Natl Cancer Inst 22; 94: 1458 1468 2 Tannock et al. N Engl J Med 24;351(15): 152-1512 3 Kantoff et al. N Engl J Med 21; 363(5): 411-422 4 de Bono et al. Lancet. 21; 376(9747): 1147-1154 5 Fizazi et al. Lancet 211; 377(9768): 813-822 6 de Bono et al. N Engl J Med 211; 346(21): 1995-25 7 Scher et al. GU ASCO 212 (abst) 8 Parker et al. ESMO 211 (abst)

Challenges to Developing New Drugs for Advanced Prostate Cancer

Bone Metastases Are Difficult to Evaluate Pathologic Fracture Radiotherapy to Bone Surgery to Bone Spinal Cord Compression Skeletal-Related Events (SREs)

Bone Flare With PSA Decline Ryan CJ, et al. Clin Cancer Res. 211;17:4854-4861

Challenges to Developing New Drugs for Advanced Prostate Cancer OS only accepted outcome measure PSA Circulating tumor cells (CTC) Disseminated tumor cells (DTC) Cancer stem cells (CSC) Inter-patient molecular heterogeneity ETS gene rearrangements (4%-7%) PTEN loss cancers (>5%) RAF rearrangements (~5%) BRCA carrier cancers (<1%) PCWG2* (Prostate Working Group Guidelines 2) Lack of surrogate markers * 1 Scher HI et al. J Clin Oncol. 28;26:1148-1159

Fall in Circutating Tumor Cells (CTC) Count (>5 to <5) Associated With Improved OS Median OS in Probability of Survival (%) 1 9 8 7 6 5 4 3 2 1 Group 1 Group 2 Group 3 Group 4 Curve Log-rank Comparison P-Value* 1 vs 2.1528 1 vs 3 <.1 1 vs 4 <.1 2 vs 3 <.1 2 vs 4 <.1 3 vs 4.513 2 4 6 8 1 12 14 16 18 2 22 24 26 28 3 Time from Baseline Blood Draw (Months) 88 45 26 71 *P-values not adjusted for multiple hypothesis tests 87 45 26 65 84 45 24 57 84 44 2 42 8 41 17 31 Group Description N (%) Months (95% CI) 1 <5 CTC at all draws 88 (38) >26 (21.4 to ------) 2 > 5 CTC at BL & <5 CTC at last draw 45 (2) 21.3 (18.4 to ------) 3 <5 CTC at early draw & > 5 CTC at last draw 26 (11) 9.3 (8.2 to 11.3) 4 > 5 CTC at all draws 71 (31) 6.8 (5.8 to 1.3) Cox HR (95% CI) = 2.2 (1.9-2.6) chi-square = 11.9 (P-value <.1) 76 35 1 28 71 58 47 36 32 25 2 13 7 5 4 3 18 12 7 5 No. of Patients Still at Risk 3 21 9 2 2 7 4 1 4 2 3 1 1 1 2 21.3m 6.8m de Bono JS et al. Clin Cancer Res. 28;14:632-639

Targeting the Androgen Receptor (AR)

Direct Measurement of Tissue Androgens Confirm the Presence of Sufficient Levels to Activate the Receptor

The New Antiandrogens Abiraterone Acetate (Phase 3 studies post- and pre-docetaxel) - Potent and selective inhibitor of CYP17-α-hydroxylase and C17,2-lyase MDV31 (Phase 3 studies post- and pre-docetaxel) - AR antagonist, inhibits nuclear translocation and blocks DNA binding of the receptor and activation TAK-7 (Phase 3 studies post- and pre-docetaxel) - Selective, nonsteroidal, small-molecule inhibitor of 17,2-lyase TOK-1 (Phase 1/2 ARMOR1) - AR antagonist, and AR degrader, and a CYP17 lyase inhibitor SARDS - Selective androgen receptor degraders (destroy the AR receptor) ARN-59 (Phase 1/2) - AR antagonist, inhibits nuclear translocation and DNA binding of the receptor Co-factor antagonists -Target coactivator interaction surfaces AR antagonists

Abiraterone Inhibits Androgen Biosynthesis Through CYP17 Androgens produced at 3 critical sites Testes Adrenal gland Prostate tumor cells Abiraterone inhibits biosynthesis of androgens that stimulate tumor cell growth PSA and radiographic responses in Phase 2 studies of CRPC Chemo-naïve and post-chemo patients 1-6 1. Attard G et al. J Clin Oncol. 28;26:4563-4571; 2. Attard G et al. J Clin Oncol. 29;27:3742-3748; 3. Reid AH et al. J Clin Oncol. 21;28:1489-1495; 4. Ryan CJ et al. J Clin Oncol. 21;28:1481-1488; 5. Danila DC et al. J Clin Oncol. 21;28:1496-151; 6. de Bono JS et al. Ann Oncol. 21;21(suppl 8): Abstract LBA5.

CRPC: Suppression of androgen levels LHRH agonists LH ACTH Abiraterone Testosterone Androstenedione Ligand-dependent Receptor tyrosine kinase Ligand-independent 4 Ligand-independent activation of AR Abiraterone 1 2 Alternate ligands Nuclear localisation Transcription Nucleus Coactivators Corepressors 5 6 7 AR splice variants Cytoplasm

Abiraterone Acetate Phase 3 Post-Chemo Study Design Efficacy endpoints (ITT) 1195 patients with progressive mcrpc Failed 1 or 2 chemotherapy regimens, 1 with docetaxel R A N D O M I Z E D 2:1 Abiraterone 1 mg daily Prednisone 5 mg bid n = 797 Placebo daily Prednisone 5 mg bid n = 398 1 endpoint: OS (25% improvement; HR.8) 2 nd endpoints: TTPP rpfs PSA response Phase 3 multicenter, randomized, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada) Stratification by: ECOG performance status -1 vs 2 Worst pain over previous 24 hours Prior chemotherapy 1 vs 2 BPI short form; -3 (absent) vs 4-1 (present) Type of progression PSA only vs radiographic with or without PSA de Bono JS et al. N Engl J Med. 211;364:1995-25.

Baseline demographics (N=1195) AA (n=797) Placebo (n=398) Median age, years (range) 69. (42-95) 69. (39-9) Caucasian 93% 92.7% ECOG-PS 2 1% 11% Significant pain present 45% 45% 2 prior chemotherapies 3% 31% Radiographic progression 7% 69% de Bono et al. N Engl J Med 211; 346(21): 1995-25

Disease sites and baseline laboratory parameters Extent of disease AA (n=797) Placebo (n=398) Bone 89% 9% Node 45% 41% Liver 11% 8% Lung 13% 11% PSA (median, ng/ml) 128.8 137.7 Hemoglobin (median, g/dl) 11.8 11.8 Alkaline phos (median, IU/L) 133.5 134. LDH (median, IU/L) 223. 237.5 de Bono et al. N Engl J Med 211; 346(21): 1995-25

Overall survival: Interim analysis Survival (%) 1 8 6 4 2 HR (95% CI):.65 (.54-.77) p<.1 Placebo: 1.9 months (95% CI, 1.2-12.) AA Placebo Abiraterone acetate: 14.8 months (95% CI, 14.1-15.4) Median follow-up 12.8 months 3 6 9 12 15 18 21 Time to Death (Months) AA 797 736 657 52 282 68 2 Placebo 398 355 36 21 15 3 3 de Bono et al. N Engl J Med 211; 346(21): 1995-25

Overall survival: second pre-planned analysis (775 Events) 1 Median OS benefit of AA from 3.9 to 4.6 months Survival (%) 8 6 4 2 Placebo median OS (95% CI): 11.2 months (1.41-13.14) HR (95% CI):.74 (.638-.859) p<.1 AA median OS (95% CI): 15.8 months (14.82-17.2) Placebo AA Median follow-up 2.2 months 6 12 18 24 3 Time to Death (Months) AA 797 657 473 273 15 Placebo 398 36 183 1 6 Scher et al. J Clin Oncol 211; 29 (suppl): Abstract LBA4517

Survival Benefit Consistently Observed Across Patient Subgroups Variable Subgroup N HR 95% CI All subjects All 1195.66.56-.79 Baseline ECOG -1 168.64.53-.78 2 127.81.53-1.24 Baseline BPI < 4 659.64.5-.82 4 536.68.53-.85 No of prior chemotherapy regimens 1 833.63.51-.78 2 362.74.55-.99 Type of progression PSA only 363.59.42-.82 Radiographic 832.69.56-.84 Age, years < 65.66.48-.91 65.67.55-.82 Visceral disease at entry Yes 353.7.52-.94 Baseline PSA above median Yes 591.65.52-.81 Baseline LDH above median Yes 581.71.58-.88 Baseline ALK-P above median Yes 587.6.48-.74 Region N America 652.64.51-.8 Other 543.69.54-.9 Favors AA.5.75 1 1.5 Favors placebo de Bono et al. N Engl J Med 211; 346(21): 1995-25

Survival By Baseline Stratification Factors: Prior Chemotherapy 1 prior line of chemotherapy 2 prior lines of chemotherapy 1 1 Survival (%) 8 6 4 Abiraterone acetate: 15.4 months Survival (%) 8 6 4 Abiraterone acetate: 14. months 2 AA Placebo Placebo: 11.5 months 3 6 9 12 15 18 21 Time to Death (Months) 2 AA Placebo Placebo: 1.3 months 3 6 9 12 15 18 21 Time to Death (Months) Median overall survival - Abiraterone acetate (AA) vs placebo 1 prior line of chemotherapy: 15.4 vs 11.5 months 2 prior lines of chemotherapy: 14. vs 1.3 months se Bono JS, et al. ESMO 21; Abstract P135. Scher HI, et al. ASCO GU 211; Abstract 4.

Survival By Baseline Stratification Factors: ECOG Status Survival (%) 1 8 6 4 2 Placebo: 7 months AA, ECOG -1 Placebo, ECOG -1 AA, ECOG 2 Placebo, ECOG 2 Eastern Cooperative Oncology Group (ECOG) status (-1 vs 2) AA: 7.3 months Placebo: 11.7 months Abiraterone acetate: 15.3 months 3 6 9 12 15 18 21 Time to Death (Months) Median overall survival - Abiraterone acetate (AA) vs placebo ECOG -1: 15.3 vs 11.7 months ECOG 2: 7.3 vs 7 months Scher HI, et al. ASCO GU 211; Abstract 4.

Survival By Baseline Stratification Factors: Pain 1 Pain (-3 [absent]) 1 Pain (4-1 [present]) Survival (%) 8 6 4 Placebo: 2 13 months AA Placebo 3 6 9 12 15 18 21 Time to Death (Months) Abiraterone acetate: 16.2 months Survival (%) 8 6 4 2 Placebo: 8.9 months Abiraterone acetate: 12.6 months AA Placebo 3 6 9 12 15 18 21 Time to Death (Months) Median overall survival - Abiraterone acetate (AA) vs placebo Without pain: 16.2 months vs 13 months With pain: 12.6 months vs 8.9 months Scher HI, et al. ASCO GU 211; Abstract 4.

All Secondary End Points Achieved Statistical Significance AA (n = 797) Placebo (n = 398) HR (95% CI) P Value TTPP (months) 1.2 6.6.58 (.46,.73) rpfs (months) 5.6 3.6.67 (.59,.78) <.1 <.1 ORR (%) a 14. (n=55/392) 2.8 (n=5/181) 5.1 b (2.1-12.5) <.1 PSA response rate Total 38.% 1.1% <.1 Confirmed 29.1% 5.5% <.1 a RECIST in subjects with measureable disease t baseline; b relative risk; AA, abiraterone acetate; CI, confidence interval; HR, hazard ratio; PSA, ORR, objective response rate; prostate-specific antigen; TTPP, time to PSA progression; rpfs, radiographic progression-free survival.

Survival benefit in patients with favorable and unfavorable CTC counts at baseline Proportion Survival 1..75.5.25. Baseline CTC <5 Sample Size: AA CTC <5 314 Placebo CTC <5 141 AA Median (95% CI): 22.1 Months (2.4-24.1) Placebo Median (95% CI): 19.7 Months (16.7-not estimable) 5 1 15 2 25 3 Overall Survival (Months) Placebo AA N=972 a Proportion Survival 1..75.5.25. Baseline CTC 5 AA Median (95% CI): 1.9 Months (9.9-12.) Placebo Median (95% CI): 8.2 Months (7.4-9.3) 5 1 15 2 25 3 Overall Survival (Months) Placebo Sample Size: AA CTC 5 335 Placebo CTC 5 182 AA N=972 a a Missing baseline CTC patients excluded a Missing baseline CTC patients excluded Scher et al. J Clin Oncol 211; 29 (suppl): Abstract LBA4517

Higher conversion rates from unfavorable ( 5 CTC) to favorable (<5 CTC) Week 4 Week 8 Week 12 No. of patients with baseline CTC 5 and a postbaseline CTC value 422 374 33 Conversion status AA (n=272) Placebo (n=15) AA (n=245) Placebo (n=129) AA (n=217) Placebo (n=113) Conversion 42% 14% 5% 17% 48% 17% (n) (113) (21) (123) (22) (15) (19) p value <.1 <.1 <.1 p value from chi-square statistic Scher et al. J Clin Oncol 211; 29 (suppl): Abstract LBA4517)

Adverse Events of Special Interest AA (n = 791) All Grades Grades 3/4 Placebo (n = 394) All Grades Grades 3/4 Fluid retention 3.5% 2.3% 22.3% 1.% Hypokalemia 17.1% 3.8% 8.4%.8% LFT abnormalities 1.4% 3.5% 8.1% 3.% Hypertension 9.7% 1.3% 7.9%.3% Cardiac 13.3% 4.1% 1.4% 2.3% disorders a A Most frequently reported cardiac terms were tachycardia and atrial fibrillation. The rate of grade 5 lethal cardiac events was identical in the 2 study arms: 1.3% (1 pts) in AA and 1.3% (5 pts) in placebo.

Symptomatic Improvement: Pain Intensity Palliation (BPI) Brief Pain Inventory Questionnaire Patients Experiencing Palliation 7% 6% 5% 4% 3% 2% 1% % P =.2 155/349 (44.4%) 44/163 (27.%) Abiraterone Acetate Placebo Logothetis C, et al. ASCO 211; Abstract 452.

Pain Alteration and Improvement Study Regimen Pain scale Response definition with Caveats N Pain response Duration Tannock, JCO, 1996 Mito/pred vs. pred PPI 2 point reduction for 3 weeks 161 29% vs. 12% p=.1 43 weeks vs. 18 weeks p<.1 TAX 327, Tannock NEJM Doce/pred vs. Mito/pred PPI 2 point reduction for 3 weeks 16 (45% with pain) 35% vs. 22% p=.1 (q 3 week arm) 3.5 vs. 4.8 mos (no difference) TROPIC, Sartor Lancet 21 CBZ/pred vs. mito/pred PPI 2 point reduction for 3 weeks 755 (45% with pain) 9.2% vs. 7.7% p=.63 Median time to pain progression not reached Cougar 31, Logothetis, ASCO 211 Abi/pred vs. placebo/pred BPI 3% reduction from baseline over 4 weeks 1195 (44% with pain) 44.4% vs. 27% p=.2 25 th percentile: 8 mos vs. 5 mos p=.56

Pain Alteration and Improvement Study Regimen Pain scale Response definition with Caveats N Pain response Duration Tannock, JCO, 1996 Mito/pred vs. pred PPI 2 point reduction for 3 weeks 161 29% vs. 12% p=.1 43 weeks vs. 18 weeks p<.1 TAX 327, Tannock NEJM Doce/pred vs. Mito/pred PPI 2 point reduction for 3 weeks 16 (45% with pain) 35% vs. 22% p=.1 (q 3 week arm) 3.5 vs. 4.8 mos (no difference) TROPIC, Sartor Lancet 21 CBZ/pred vs. mito/pred PPI 2 point reduction for 3 weeks 755 (45% with pain) 9.2% vs. 7.7% p=.63 Median time to pain progression not reached Cougar 31, Logothetis, ASCO 211 Abi/pred vs. placebo/pred BPI 3% reduction from baseline over 4 weeks 1195 (44% with pain) 44.4% vs. 27% p=.2 25 th percentile: 8 mos vs. 5 mos p=.56

Pain Alteration and Improvement Clinical benefit with AA over placebo for treatment of bone metastases: Improved pain palliation Delayed pain progression Delayed time to SRE Effect sustained over treatment cycles. Logothetis C, et al. ASCO 211; Abstract 452.

Fatigue Analysis: Abiraterone Significantly Improved Fatigue Outcomes AA + prednisone (n = 797) Placebo + prednisone (n = 398) P =.1 P =.96 221/384 75/186 13/189 35/92 Baseline Brief Fatigue Inventory (BFI) scores for all items on the questionnaire were not different between groups: Fatigue intensity a : 3.78 vs 3.62 for AA + prednisone vs P + prednisone (P =.278) Fatigue interference b : 3.5 vs 2.9 for AA + prednisone vs P + prednisone (P =.444) AA + prednisone - significantly better fatigue outcomes (fatigue intensity and fatigue interference) more rapidly than placebo and prednisone a Item 3 on the BFI questionnaire. b Average of items 4A-4F on the BFI questionnaire. Sternberg CN, et al. ESMO, 211, September 23-27, 211. Abstract 7.15

Fatigue Analysis: Progression of Both Fatigue Intensity and Interference Were Significantly Delayed AA + prednisone (n = 797) Placebo + prednisone (n = 398) A B 1. 1. Proportion without fatigue progression (intensity).8.6.4.2 25 th Percentile: 139 days 25 th Percentile: 232 days P <.1 HR:.67 (.52-.86) Proportion without fatigue progression (interference).8.6.4.2 25 th Percentile: 139 days 25 th Percentile: 281 days P <.1 HR:.67 (.52-.86). 1 2 3 4 5. 1 2 3 4 5 Time (Days) Time (Days) Abiraterone significantly delayed progression of both fatigue intensity and interference Sternberg CN, et al. ESMO, 211, September 23-27, 211. Abstract 7.15

Abiraterone Delayed Time to Deterioration of Quality of Life AA + prednisone (n = 797) Placebo + prednisone (n = 398) Median Time to Decline (Days) 45 4 35 3 25 2 15 1 5 * * P =.325 * * 363 253 339 24 168 89 424 226 337 169 424 274 262 142 395 253 * * * WB, well-being; FACT-P, Functional Assessment of Cancer Therapy-general quality of life; PCS, Prostate Cancer Subscale; TOI, Trial Outcome Index. *P <.1 Harland S, et al. ESMO, 211, September 23-27, 211, Stockholm, Sweden. Abstract 7.1

Clinical Need in CRPC An intervention with little or no toxicity compared to chemotherapy for asymptomatic or mildly symptomatic CRPC Aim to prevent or delay the onset of pain related to metastatic disease and disease progression Prolong survival

Abiraterone in pre-chemotherapy setting Anti-tumor activity in phase 1/2: Prechemotherapy (n = 42) 5% PSA decline 67% Radiological findings Partial response 37.5% Stable disease 66% Favorable CTC conversion Phase 1/2 59% Median TTPP (days) 225 n = 1 Asymptomatic or mildly symptomatic patients with CRPC Phase 3 COU-AA-32 is a phase 3 randomised, double-blind, placebocontrolled trial in CRPC patients pre-chemotherapy Co-primary endpoints: OS and PFS R 1:1 Abiraterone 1 mg qd + prednisone 5 mg bid Placebo qd + prednisone 5 mg bid CTC, circulating tumor cell TTPP, median time to PSA progression Accrual completed 4/29 www.clinicaltrials.gov. NCT887198.

Phase 3 Trial of Abiraterone Acetate in Asymptomatic or Mildly Symptomatic mcrpc Pre-Chemotherapy (n = 1) mcrpc ECOG PS or 1 bone mets or lymph nodes R A N D O M I Z E 1:1 Abiraterone acetate, 1 mg/day + prednisone/prednisolone 5 mg PO bid Prednisone/prednisolone 5 mg PO bid + placebo Primary endpoint: OS and PFS Secondary: clinical improvement, safety profile, PK Accrual completed 4/29 www.clinicaltrials.gov. NCT887198.

How will new hormonal treatments be integrated into the treatment schema? Abiraterone (COU-AA-32) MDV31 (PREVAIL) TAK-7 (NCT1193244) Tasquinimod (NCT1234311) Ipilimumab (NCT15781) Radium-223 (ALSYMPCA) Not approved Approved Custirsen (SYNERGY) Cabazitaxel (FIRSTANA) Dasatinib (NCT744497) Aflibercept (VENICE) Docetaxel (TAX 327) Mitoxantrone (TAX 327) MDV31 (AFFIRM interim) Ipilimumab (NCT861614) TAK-7 (NCT1193257) Radium-223 (ALSYMPCA) Cabazitaxel (TROPIC) Abiraterone (COU-AA-32) No metastases Metastases Pre-docetaxel Docetaxel Post-docetaxel Death

Conclusions in mcrpc Unequivocal evidence of continued involvement of the AR signaling axis Abiraterone prolongs OS in mcrpc - who have progressed after docetaxel-based chemotherapy - 26% risk reduction of death (HR =.74) Abiraterone significantly improves TTPP, rpfs, and PSA response rate Prostate cancer is not yet a chronic disease, but we are making progress! Stermnberg CN, ESMO Presidential symposium October 21