Trial Level Analysis of Prostate-Specific Antigen-Related Versus Unrelated Endpoints in Phase III Trials of First-Line and Second-Line Medical Treatments of Patients With Metastatic Castration-Resistant Prostate Cancer.
No endpoint (EP) has yet been recognized as a surrogate of overall survival (OS) after systemic treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of the present report was to suggest, using a trial-level analysis, what might be the most appropriate EPs for trials of new drugs for patients with mCRPC.



A literature search of randomized trials of medical treatments in patients with mCRPC was undertaken. The response-related and time-to-event EPs were evaluated. For each trial, the differences in OS and the examined EPs between the experimental and control arms and a correlation coefficient for every relationship were calculated. An additional regression analysis was performed to determine the proportion of variability explained (R2trial) on OS for the most frequently reported EPs in the selected trials.



A total of 28 studies were included in the present analysis. Correlation analyses documented a significant relationship between the prostate-specific antigen (PSA)-related response rate and OS. Although not significant, a strong correlation coefficient was found for the relationship of radiologic progression-free survival (PFS) and OS and of PSA-related PFS and OS. The strength of the relationships with OS for all 3 EPs was greater among the trials published from 2005 to 2014.



The PSA response rate and radiologic PFS reported greater rates of correlation with OS among trials of medical treatments of mCRPC, in particular, in studies published in the past 10 years. Both PSA and PFS should be evaluated for surrogacy at an individual level in large prospective trials of medical treatments for patients with mCRPC.
Department of Medical Oncology, Giovanni Borea Hospital, Sanremo, Italy. Electronic address: ga.colloca@libero.it.
Giuseppe
G
Colloca
Department of Radiotherapy, Ospedali Riuniti, Ancona, Italy.
Pasquale
P
Vitucci
Department of Medical Oncology, Giovanni Borea Hospital, Sanremo, Italy.
Antonella
A
Venturino
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism*; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D017430:Prostate-Specific Antigen
Chemotherapy; Hormonal therapy; PSA; Progression-free survival; mCRPC