SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract on Prostate Cancer) In Oncologia

SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract on Prostate Cancer) In Oncologia Divisione di Oncologia Medica Unità Tumori Genitourinari

Agenda: 1. Sweeney C, Chen YH, Carducci MA, et al. ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED). ESMO conference 2014, abst E3805. 2. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014; 371: 424 33. 3. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy naive men with metastatic castration resistant prostate cancer (COU AA 302): final overall survival analysis of a randomised, double blind, placebo controlled phase 3 study. Lancet Oncol. 2015; 16: 152 60. 4. Antonarakis ES, Lu C, Wang H, et al. AR V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014; 371:1028 38.

The CHAARTED Hypothesis s Docetaxel added at the time of starting androgen deprivation therapy for hormone naïve metastatic prostate cancer will prolong overall survival High volume: visceral metastases Definition of High Volume and/or 4 or more bone metastases with at least 1 beyond pelvis andvertebral column At inception, only patients with high volume disease were to be accrued

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 Yes vs No Prior Adjuvant ADT 12 vs > 12 months R A N D O M I Z E ARM A: ADT + docetaxel 75mg/m2 every 21 days for maximum 6 cycles ARM B: ADT (androgen deprivation therapy alone) Evaluate every 3 weeks while receiving docetaxel and at week 24 then every 12 weeks Evaluate E alone) every 12 weeks Follow for time to progression and overall survival Chemotherapy at investigator s s discretion at progression ADT allowed up to 120 days prior to randomization Intermittent ADT dosing was not allowed Standard dexamethasone premedication but no daily prednisone

Metastatic prostate cancer Key Eligibility Criteria if clinical i l scenario c/w PrCa PC can enroll without t tissue Prior ADT limited to 120 days prior to randomization or adjuvant Rx < 24 months and no progression within 12 months of finish ECOG 0 2 (2 only if due to PrCa) Liver, bone marrow, renal, cardiac, pulmonary and neurological function suitable for docetaxel No prior docetaxel

Primary Endpoint Overall survival Secondary Endpoints Study Endpoints Rate of PSA < 0.2 ng/ml at 6 months and 12 months Time to biochemical, radiographic or symptomatic PD Time to radiographic or symptomatic progressive disease (PD) Define adverse event profile and tolerability Qualityoflife life (FACT P) until12monthsafter randomization

Patients characteristics:

Primary endpoint: OS

Key Eligibility Criteria 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. We projected 33 months in ADT alone arm with collaboration of SWOG 9346 team.

ADT + docetaxel benefited all subgroups with high volume disease

Hematologic Toxicity (%)

Enzalutamide, mechanism of action

Study design

Key Eligibility Criteria

Primary endpoints: PFS

Primary endpoints: OS

Subgroup analysis

Subsequent therapies

Study design Patient Population Progressive mcrpc without prior chemotherapy; Asymptomatic or mildly symptomatic a Stratification by ECOG PS 0 vs 1. R A N D O M I Z E D Abiraterone 1000 mg daily + Prednisone 5 mg BID (actual n = 546) Placebo daily + Prednisone 5mg BID Co primary end points: rpfs (central review) OS Secondary end points: Time to opiate use Time to initiation of chemotherapy Time to ECOG PS 1:1 a (actual n = 542) deterioration Time to PSA progression Final analysis: 96% of expected deaths, 741 actual deaths

Evolution of Statistical Significance Required p Value for Significance IA1 IA2 <0.00010001 0.00080008 IA3 0.0035 FA 0.0384 2009 2010 2011 2012 2013 2014 2015 IA1 0.6926 Actual p Value Observed IA2 0.0097 IA3 0.01510151?

Patients characteristics at baseline Abiraterone (n = 546) Prednisone (n = 542) Median age, years (range) 71 (44 95) 70 (44 90) Median time from initial diagnosis to first dose (years) 5.5 5.1 Median PSA (ng/ml) 42.0 37.7 Gleason score ( 8) at initial iti ldiagnosisi 54% 50% Extent of disease Pain (BPI SF) Bone metastases 83% 80% > 10 bone metastases 49% 47% Soft tissue a 49% 50% 0 1 66% 64% 2 3 32% 33% a Excludes visceral metastases. BPI SF, Brief Pain Inventory Short Form (scale 0 10).

Primary endpoints: PFS

Primary endpoints: OS Median follow up of 49.2 months Abiraterone treatment effect more pronounced when adjusting for 44% of prednisone patients who received subsequent abiraterone (HR = 0.74)

Subsequent Therapy Abiraterone n (%) Prednisone n (%) No. with selected subsequent therapy for mcrpc 365 (67) 435 (80) Abiraterone 69 (13) 238 (44) a Cabazitaxel 100 (18) 105 (19) Docetaxel 311 (57) 331 (61) Enzalutamide 87 (16) 54 (10) Ketoconazole 42 (8) 68 (13) Radium 223 20 (4) 7 (1) Sipuleucel T 45 (8) 32 (6) a Includes 93 patients who received abiraterone per protocol amendments.

Background

Key Eligibility Criteria

Baseline Characteristics Enzalutamide Patients Abiraterone Patients

PFS and PSA RR Enzalutamide Abiraterone

Antonarakis et al. ASCO GU 2015 Can AR V7 be used as predictive factor?

Fine.