Abstract 1375P
Background
We have previously shown that radiographic progression-free survival is potentially a valid surrogate of OS. Here, we explore whether castrate-resistant free survival (CRFS) and time to castrate-resistant disease (TCRD) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite phase 3 clinical trials. This hypothesis was investigated by the STOPCAP M1 Collaboration.
Methods
We obtained individual patient data (IPD) from 13/26 eligible randomized trials comparing treatment regimens (androgen deprivation therapy (ADT) or ADT + docetaxel in the control or research arms) in mHSPC. We evaluated the surrogacy of CRFS and TCRD as potential ICEs for OS. CRFS was defined as time from randomization to radiographic progression, symptoms, initiation of new treatment, biochemical progression or death from any cause, whichever occurred first; whereas TCRD used the same definition as CRFS except included prostate cancer death only. We implemented a two-stage meta-analytic validation model where conditions of trial-level and patient-level surrogacy had to be met. The surrogate threshold effect (STE), which is the minimum ICE treatment effect necessary to estimate a non-zero effect on OS.
Results
IPD from 8592 patients randomized from 1994-2012 were analyzed for a stratified analysis. There were 5377 deaths, of which 3971 (74%) were due to prostate cancer. The median follow-up for surviving patients was 6 years and 4 months. In addition, there were 8260 CRFS and 8215 TCRD events. The median OS, CRFS and TCRD were 49.4, 13.7, and 13.3 months, respectively. The STE was 0.72 for both CRFS and TTCR. Table: 1375P
| ICE | Condition 1: ICEs and OS are correlated | Condition 2: Treatment effects on both endpoints are correlated | |
| Correlation at the Patient level, Kendall's Tau (95% CI) | Regression of 5-year OS vs 1-year ICE rate R2 (95% CI) | Regression of log(HR)-OS vs. log(HR)-ICE by trial R2(95% CI) | |
| CRFS | 0.65 (0.64, 0.66) | 0.63 (0.40, 0.88) | 0.65 (0.39,0.92) |
| TCRD | 0.65 (0.64, 0.67) | 0.64 (0.41, 0.92) | 0.65 (0.40,0.91) |
HR=Hazard Ratio
Conclusions
Both CRFS and TCRD do not appear to be good surrogate endpoints of OS in mHSPC patients.
Clinical trial identification
NCT00002651, NCT00079001, NCT00104715, NCT00268476, NCT00309985, NCT00216060, ISRCTN38477744, NCT00685646.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Prostate Cancer Foundation, UK Prostate Cancer.
Disclosure
S. Halabi: Financial Interests, Personal, Other, Member of DSMB: Sanofi, Aveo Oncology; Financial Interests, Institutional, Funding: ASCO. I.M. Thompson: Financial Interests, Personal, Advisory Board: Profound Medical; Financial Interests, Personal and Institutional, Full or part-time Employment: CHRISTUS Health; Financial Interests, Personal, Member of the Board of Directors: Magenta Health, MagForce USA; Non-Financial Interests, Personal, Advisory Board: National Cancer Institute; Non-Financial Interests, Institutional, Principal Investigator: National Cancer InstituteInstitute. M.A. Carducci: Financial Interests, Personal, Other, Data Safety Monitoring Board: Pfizer; Financial Interests, Personal, Advisory Board: Exelexis; Financial Interests, Personal, Other, JCO Editor: American Society of Clinical Oncology; Financial Interests, Institutional, Invited Speaker: Arcus, Celgene; Non-Financial Interests, Leadership Role: ECOG-ACRIN. M.J. Morris: Financial Interests, Personal, Advisory Board: Oric, Pfizer, Exelixis, Lantheus, AstraZeneca, Amgen, Daiichi, Convergent; Financial Interests, Personal, Stocks/Shares: Doximity; Financial Interests, Institutional, Invited Speaker: Novartis, Corcept, Celgen, Janssen. G. Gravis Mescam: Financial Interests, Institutional, Advisory Board: AAA, Alliance Merck-Pfizer, Astellas, BMS, Janssen, Pfizer, Ipsen, Alliance Merck-Pfizer; Financial Interests, Institutional, Invited Speaker: AAA, Amgen, Astellas, BMS, Janssen, MSD, Pfizer, Sanofi, Ipsen, AstraZeneca, BMS; Financial Interests, Institutional, Funding: Janssen; Non-Financial Interests, Principal Investigator: Ipsen, BMS, Merck. M.E. Buyse: Financial Interests, Personal, Officer, Chief Scientific Officer: IDDI; Financial Interests, Personal, Invited Speaker, Board Member: CluePoints; Financial Interests, Personal, Stocks/Shares: IDDI, CluePoints. C.J. Sweeney: Financial Interests, Personal, Advisory Board, Consultancy: Genentech, Roche, Bayer, Astellas, Pfizer, Pfizer, Sanofi, Lilly; Financial Interests, Personal, Other, Consultancy: Janssen; Financial Interests, Personal, Stocks/Shares: Leuchemix; Financial Interests, Institutional, Research Grant: Bayer, Janssen, Astellas, Pfizer, Dendreon, Sanofi. All other authors have declared no conflicts of interest.