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

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

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

3 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 E Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014; 371: 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: 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:

4 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 E Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014; 371: 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: 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:

5 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

6 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

7 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

8 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

9 Patients characteristics:

10 Primary endpoint: OS

11 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.

12 ADT + docetaxel benefited all subgroups with high volume disease

13 Hematologic Toxicity (%)

14 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 E Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014; 371: 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: 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:

15 Enzalutamide, mechanism of action

16 Study design

17 Key Eligibility Criteria

18 Primary endpoints: PFS

19 Primary endpoints: OS

20 Subgroup analysis

21 Subsequent therapies

Study design Patient Population Progressive mcrpc without prior chemotherapy;

R A N D O M I Z E D Abiraterone 1000 mg daily + Prednisone 5 mg BID (actual n = 546)

Secondary end points: Time to opiate use Time to initiation of chemotherapy Time to

22 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

23 Evolution of Statistical Significance Required p Value for Significance IA1 IA2 < IA FA IA Actual p Value Observed IA IA ?

24 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) Median PSA (ng/ml) 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% % 64% % 33% a Excludes visceral metastases. BPI SF, Brief Pain Inventory Short Form (scale 0 10).

25 Primary endpoints: PFS

26 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)

27 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 E Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014; 371: 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: 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:

28 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 (4) 7 (1) Sipuleucel T 45 (8) 32 (6) a Includes 93 patients who received abiraterone per protocol amendments.

29 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 E Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014; 371: 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: 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:

30 Background

31 Key Eligibility Criteria

32 Baseline Characteristics Enzalutamide Patients Abiraterone Patients

33 PFS and PSA RR Enzalutamide Abiraterone

34 OS

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

36 Fine.

mcrpc 2014 TRA EVOLUZIONE E RIVOLUZIONE: COME ORIENTARSI NEL LABIRINTO DELLE TERAPIE

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