Clinical outcomes and survival surrogacy studies of prostate-specific antigen declines following enzalutamide in men with metastatic castration-resistant prostate cancer previously treated with docetaxel.
BACKGROUND
In the AFFIRM trial, enzalutamide significantly increased overall survival (OS) for men with metastatic castration-resistant prostate cancer (mCRPC) after chemotherapy versus placebo and significantly decreased prostate-specific antigen (PSA) levels. The goal of this post hoc analysis was to associate levels of PSA decline from baseline after enzalutamide with clinical outcomes in the postchemotherapy mCRPC setting.


METHODS
Men in the AFFIRM trial (n = 1199) were grouped by maximal PSA decline in the first 90 days of treatment. Kaplan-Meier estimates evaluated the association of defined PSA changes from baseline with OS, progression-free survival (PFS), radiographic PFS (rPFS), and pain response. Each PSA decline category was assessed for OS surrogacy using Prentice criteria, proportion of treatment effect explained (PTE), and proportion of variation explained.


RESULTS
Men treated with enzalutamide had improved OS (hazard ratio, 0.63; P < .001) and higher rates of PSA decline (odds ratio, >19.0; P < .001) versus placebo. PSA declines of any, ≥30%, ≥50%, and ≥90% with enzalutamide were strongly associated with greater OS, PSA PFS, rPFS (P < .001), and pain response (P < .026) versus PSA increase/no decline. Any, ≥30%, and ≥50% declines in PSA resulted in the PTE range of 1.07-1.29, where treatment was no longer significant after adjustment for decline measures (P > .20).


CONCLUSIONS
PSA declines of any, ≥30%, and ≥50% following enzalutamide were associated with greater clinical and pain response and improvements in PFS and OS. Surrogacy of PSA decline for OS was not fully established, possibly due to lack of PSA declines with placebo, and discordant results between PSA and imaging responses over time, and because some declines were not durable due to rapid resistance development. However, a lack of PSA decline by 90 days following enzalutamide treatment was a poor prognosis indicator in this setting. Conclusions from sensitivity analyses of maximal PSA decline from baseline over the entire treatment period are consistent with PSA declines restricted to the first 90 days. Cancer 2017;123:2303-2311. © 2017 American Cancer Society.
Duke Cancer Institute, Durham, North Carolina.
Andrew J
AJ
Armstrong
Centre Hospitalier de l'Université de Montréal and CRCHUM, Montreal, Quebec, Canada.
Fred
F
Saad
Astellas Pharma, Inc., Leiden, Netherlands.
De
Phung
Astellas Pharma, Inc., Northbrook, Illinois.
Carl
C
Dmuchowski
Carolina Urologic Research Center, Myrtle Beach, South Carolina.
Neal D
ND
Shore
Institut Gustave Roussy, University of Paris Sud, Paris, France.
Karim
K
Fizazi
Medivation, Inc., San Francisco, California.
Mohammad
M
Hirmand
Medivation, Inc., San Francisco, California.
David
D
Forer
Sidney Kimmel Center for Prostate and Urologic Cancers and Memorial Sloan-Kettering Cancer Center, New York, New York.
Howard I
HI
Scher
Institute of Cancer Research, London, UK.
Johann De
J
Bono
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D002277:Carcinoma / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D018572:Disease-Free Survival; D000077143:Docetaxel; D004311:Double-Blind Method; D006801:Humans; D007610:Kallikreins / Q000097:blood*; D053208:Kaplan-Meier Estimate; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D043823:Taxoids / Q000627:therapeutic use; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D043823:Taxoids; D000077143:Docetaxel; D010669:Phenylthiohydantoin; C540278:enzalutamide; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
enzalutamide; metastatic castration-resistant prostate cancer; prostate-specific antigen; surrogate endpoint; survival