Should we use Docetaxel in hormone- naïve prostate cancer? Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France

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1 Should we use Docetaxel in hormone- naïve prostate cancer? Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France

2 Disclosure Participation to advisory boards/honorarium from: Amgen, Astellas, Bayer, Ipsen, Janssen, Takeda, Novartis, Sanofi, Orion

3 Docetaxel improves Overall Survival in CRPC (2004) True but: - Benefit is limited (HR=0.76; median: 2-3 months) - Not all patients can receive it (too old, too sick) Tannock IF, et al: NEJM 351: , 2004

4 Incidence of de novo metastatic prostate cancer 5-30% <5% 70% Wu JN, Cancer 2014; 120:

5 Metastatic hormone- naïve prostate cancer: 2 scenarios Local cancer PSA failure No salvage hormonal therapy Scenario 1: quite rare: - 27% in Chaarted - 28% in GETUG 15 Metastatic hormone- naïve prostate cancer De Novo Scenario 2: more frequent: - 73% in Chaarted - 72% in GETUG 15

6 What are the data?

7 Three available phase III trials: GETUG 15, Chaarted and Stampede METASTATIC HORMONE-NAÏVE PROSTATE CANCER ARM A: ADT + docetaxel 75mg/m2/21 d x 6/9 cycles MAIN STRATIFICATION FACTORS: Extent of disease ECOG PS Prior Adjuvant ADT RA ND OM IZE ARM B: ADT (androgen deprivation therapy alone) GETUG 15 n=385 Accrual: Chaarted n= 790 Accrual:

8 Docetaxel in HSPC: Clinical PFS is improved GETUG 15: Chaarted: Median: 15 vs 23 months Median: 19.8 vs 32.7 months HR: 0.75 [ ] p=0.015 HR=0.49 ( ) (<0.0001) Gravis G, Lancet Oncol 2013; 14: Sweeney C, N Engl J Med 2015

9 Docetaxel in HSPC: Overall Survival GETUG 15 (1/2 poor risk pts) ADT + D: 61 months ADT: 47 months HR: 0.9 [ ]; p=0.44 Chaarted (2/3 poor risk pts) ADT + D: 58 months ADT alone: 44 months HR=0.61 ( ) p= Gravis G, Lancet Oncol 2013; 14: Gravis G, ASCO GU 2015 Sweeney C, ASCO 2014

10 CHAARTED: OS by Disease Extent (volume) Sweeney C, et al. N Engl J Med. 2015;373:

11 Patient s price: What is the price to pay for this clinical benefit? Classical docetaxel toxicity Toxicity- related deaths: 3/455 (0.7%) Society: Docetaxel=generic Large magnitude of clinical/survival benefit Likely very cost- effective

12 Stampede: Docetaxel: Survival M1 Patients SOC SOC+Doc 343 deaths 134 deaths SOC+Doc HR (95%CI) 0.73 (0.59, 0.89) P- value SOC Non- PH p- value 0.23 Median OS (95% CI) SOC 43m (24, 88m) SOC+Doc 65m (27, NR) Restricted mean OS time SOC 49.3m SOC+Doc 56.1m Diff (95%CI) 6.8m (2.8, 11.0m) James N, ASCO 2015

13 M1 docetaxel: Survival Results based on 2993 men / 1254 deaths Trial name CHAARTED GETUG15 STAMPEDE (SOC +/- Doc) STAMPEDE (SOC+ZA +/- Doc) Overall Favours SOC + docetaxel HR=0.77 (0.68, 0.87) p< Favours SOC Heterogeneity:χ 2 =4.80, df=3, p=0.187, I 2 = 37.5% 10% absolute improvement in survival (from 40% to 50%) at 4 years Vale C, ECC 2015

14 The OS benefit of first- line chemotherapy in breast cancer, NSCLC, CRC Breast cancer: Docetaxel NSCLC: Chemotherapy vs BSC Colo- rectal cancer: Irinotecan Prostate (Chaarted) MONTHS NSCLC Meta- Analyses Collaborative Group J Clin Oncol 2008 Nabholtz JM, J Clin Oncol 2003; 21: Douillard JY, Lancet 2000; 355:

15 Some patients with metastatic hormone- sensitive prostate cancer may not be willing/are too frail to receive docetaxel

16 PEACE-1: European Phase III Trial of Abiraterone and local RXT in patients with de novo metastatic prostate cancer Androgen deprivation therapy (ADT) Patients with newly diagnosed (hormone naïve) metastatic CaP 916 patients planned R A N D O M I Z E D ADT + Abiraterone 1000mg Prednisone 5mg BID ADT + Local radiotherapy Co-primary endpoints: OS and PFS (HR: 0.75) ADT + Local radiotherapy + Abiraterone-Pred Study sponsor: Unicancer NCT

17 Systemic treatment for high- risk localized prostate cancer? (beside ADT with RXT)

18 High-risk prostate cancer GETUG 12 trial Stratification: - Gleason 8 - PSA>20 - T3 - pn+ / pn- RA ND OM I ZE ADT (3 years) + RXT Docetaxel + Estramustine (4 cycles) ADT (3 years) + RXT Primary endpoint: Progression-free survival n = 413 pts (Accrual: )

19 Docetaxel in localized CaP: Relapse-free survival (GETUG 12) HR=0.71 [ ] p= % [52-69] 50% [44-57] Fizazi K, Lancet Oncol 2015

20 RTOG 0521 Stage Any T stage High Risk Gleason score PSA 9 < T2 8 <20 R a n d o m i z e Arm 1 Androgen Suppression (24 mos) + External RT (8 wks) Arm 2 Androgen Suppression (24 mos) + External RT (8 wks) + Docetaxel beginning 4 wks after RT (6 cycles)

21 RTOG 0521: Disease-Free Survival 6 yr DFS 65% vs. 55% HR 0.76 (95%CI: ) Sandler H, ASCO 2015

22 M0 docetaxel: Failure free survival Results based on 2348 men / 842 events Trial name GETUG 12 RTOG 0521 STAMPEDE (SOC +/- Doc) STAMPEDE (SOC+ZA +/- Doc) TAX 3501 (Immediate ADT) TAX 3501 (Delayed ADT) Overall HR=0.70 (0.61, 0.81), p< Favours SOC + docetaxel Heterogeneity:χ 2 =2.63, df=5, p=0.757, I 2 =0% Favours SOC 8% absolute reduction in failure (from 70% to 62%) at 4 years Dale C, ECC 2015

23 PEACE-2: European Phase III Trial of Cabazitaxel and Pelvic irradiation in patients with high-risk localized prostate cancer Pts with high-risk localized CaP: at least 2 of the following criteria: Gleason 8 T3 PSA>20 ng/ml R A N D O M I Z E D N= 1050 pts planned Study sponsor: Unicancer Planned accrual duration: 4 years Androgen deprivation therapy (ADT) x 3 y + RXT (prostate) ADT + RXT (Pelvis) ADT + Cabazitaxel x 4 cycles + RXT (prostate) ADT + Cabazitaxel x 4 cycles + RXT (Pelvis) Primary end point: cpfs (HR: 070) Secondary endpoints: PSA response at 3 months bpfs Metastases-free survival CaP-specific survival OS Acute/Lg term tolerance QoL Biomarkers (biopsy) NCT

24 Chemotherapy combined with ADT for metastatic hormone- sensitive prostate cancer? YES, New standard of care! (for fit patients) Next question: should we use taxanes even earlier in patients with localized CaP and a high risk of relapse?