1837P - Assessing PSA

Background

Prior data have shown that prostate specific antigen (PSA) ≤ 0.2 ng/dL with androgen deprivation therapy (ADT) is prognostic for OS. We explored whether PSA ≤ 0.2 ng/dL at 4-7 months post randomization is a valid surrogate for OS in men with mHSPC. If so, it could be used to expedite phase 3 clinical trials. This hypothesis was investigated by the STOPCAP M1 Collaboration.

Methods

Individual patient data (IPD) from 13 eligible randomized trials comparing treatment regimens (ADT or docetaxel in the control or research arms in mHSPC) were utilized. We considered PSA measurements collected post randomization and evaluated the surrogacy of PSA ≤ 0.2 ng/dL at 4-7 months at the patient and trial levels. We utilized the proportional hazards model and estimated the hazard ratios (HR) for PSA ≤ 0.2 ng/dL predicting OS. We also fitted weighted linear regression, stratified by trial and treatment arm, and computed R² to quantify the proportion of variance that was explained by the regressions. We defined a priori clinically relevant surrogacy of R² value greater than 0.75. Lastly, we computed the surrogate threshold effect (STE), which is the minimum PSA treatment effect necessary to estimate a non-zero effect on OS.

Results

IPD from 5513 pts randomized from 1994-2012 from 13 trials were pooled for a stratified analysis. There were 3324 deaths, of which 70.5% were due to prostate cancer. The median follow-up was 74 months. At 4-7 months, the proportion of patients who had PSA ≤0.2 was 25.8%. At the individual level, PSA ≤0.2 ng/dL was a strong predictor of OS. Median OS in patients who experienced PSA≤0.2 and the results for the surrogacy analysis are presented in the table.

Table: 1837P

Conclusions

PSA≤0.2 ng/dL at 4-7 months met the surrogacy criteria and appears to be a valid surrogate endpoint for OS in men with mHSPC treated with ADT as back-bone hormonal therapy. Validation of this endpoint in trials with drugs having other mechanisms of action is planned.

Clinical trial identification

NCT00002651, NCT00216060, NCT00079001, NCT00104715, NCT00268476, NCT00309985, 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, BMS, Janssen; Financial Interests, Institutional, Funding: ASCO. M.K. Parmar: Financial Interests, Institutional, Full or part-time Employment, Director at MRC Clinical Trials Unit at UCL: Medical Research Council Clinical Trials Unit at UCL; Financial Interests, Institutional, Research Grant: AstraZeneca, Astellas, Janssen, Clovis; Non-Financial Interests, Advisory Role, Euro Ewing Consortium: University College London; Non-Financial Interests, Advisory Role, rEECur: University of Birmingham; Non-Financial Interests, Advisory Role, CompARE Trial: University of Birmingham. M. Hussain: Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen Pharmaceuticals, Merck & Co, Novartis, Pfizer, Bayer, Tempus Health, Convergent; Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca, Medscape, Merck, MLI Peer View, Research To Practice (RTP), Great Debates and Updates in GU Oncology; Financial Interests, Institutional, Research Funding: Arvinas, AstraZeneca, Bayer, Genentech. I.M. Thompson: Financial Interests, Personal, Coordinating PI, Clinical trial. Relationship has ended: Magforce; Financial Interests, Personal, Steering Committee Member, investigator in clinical trial: AbbVie. M.J. Morris: Financial Interests, Personal, Advisory Board: Oric, Pfizer, Exelixis, Lantheus, AstraZeneca, Amgen, Daiichi Sankyo, Convergent, Clarity Pharmaceuticals, Blue Earth Diagnostics, POINT Biopharma, Telix, Z-alpha; Financial Interests, Personal, Invited Speaker: Progenics, ITM Isotope Technologies; Financial Interests, Personal, Stocks/Shares: Doximity; Financial Interests, Institutional, Coordinating PI: Novartis, Celgen; Financial Interests, Institutional, Local PI: Corcept, Janssen, Astellas; Non-Financial Interests, Advisory Role: Bayer, Janssen Oncology, Novartis; Other, Other, Travel to conference: AstraZeneca; Other, Other, Travel/lodging at conference: APCCC. G. Gravis: Financial Interests, Institutional, Invited Speaker: AAA, Amgen, Astellas, BMS, Janssen, MSD, Pfizer, Ipsen, AstraZeneca alliance Merck Pfizer, Bayer, Eisai; Financial Interests, Institutional, Advisory Board: Alliance Merck-Pfizer, BMS, Janssen, Pfizer, ipsen, Bayer, Eisai; Non-Financial Interests, Principal Investigator: BMS, Ipsen, Merck; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Coordinating PI: BMS. D. Dearnaley: Financial Interests, Personal, Advisory Role: Janssen Pharma; Financial Interests, Institutional, Research Grant: Cancer Research UK, National Institute for Health Research (NIHR) Biomedical Research Centre; Financial Interests, Personal, Proprietary Information: ICR. N.D. James: Financial Interests, Personal, Advisory Board, Advice around PARP inhibitors: AstraZeneca; Financial Interests, Personal, Advisory Board, Prostate cancer therapies: Janssen, Clovis, Novartis; Financial Interests, Institutional, Advisory Board, Assisted with submissions regarding licencing for abiraterone: Janssen; Financial Interests, Personal, Advisory Board, Docetaxel: Sanofi; Financial Interests, Institutional, Advisory Board, Providing STAMPEDE trial data to facilitate licence extensions internationally for docetaxel: Sanofi; Financial Interests, Personal, Advisory Board, Bladder cancer therapy: Merck; Financial Interests, Personal, Advisory Board, Advice around novel hormone therapies for prostate cancer: Bayer; Financial Interests, Personal, Invited Speaker, Lecture tour in Brazil August 2022 - speaking on therapy for advanced prostate cancer: Merck Sharp & Dohme (UK) Limited; Financial Interests, Institutional, Coordinating PI, Funding for STAMPEDE trial: Janssen, Astellas; Financial Interests, Institutional, Coordinating PI, Funding for RADIO trial bladder cancer: AstraZeneca. M.E. Buyse: Financial Interests, Personal, Stocks or ownership: IDDI. C. Sweeney: Financial Interests, Personal, Advisory Board, Consultancy: Genentech Roche, Bayer, Astellas, Pfizer, Pfizer, Sanofi, Lilly; Financial Interests, Personal, Other, Consultancy: Janssen; Financial Interests, Personal, Advisory Board: Point, Cellcentric; 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.