Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer.
OBJECTIVE
It is currently unclear if early prostate-specific antigen (PSA) or pain improvements are adequate surrogates for overall survival in men with metastatic hormone-refractory prostate cancer (HRPC). Here we examined various degrees of PSA decline and pain response as surrogates for the survival benefit observed in the TAX327 trial.


METHODS
In the TAX327 trial, 1,006 men with HRPC were randomly assigned to receive docetaxel in two schedules, or mitoxantrone, each with prednisone: 989 men provided data on 3-month PSA decline. Surrogacy was examined for post-treatment changes in PSA and pain response using Cox proportional hazards models to calculate the proportion of treatment effect (PTE) explained by each potential surrogate.


RESULTS
A > or = 30% PSA decline within 3 months of treatment initiation provides the highest degree of surrogacy, with a PTE of 0.66 (95% CI, 0.23 to 1.0), and was associated with a hazard ratio (HR) of 0.50 (95% CI, 0.43 to 0.58) for overall survival after adjusting for treatment effect. Introduction of a > or = 30% PSA decline is predictive of survival regardless of treatment arm. Other changes in PSA or PSA kinetics, PSA normalization, and pain responses were highly prognostic but weaker surrogates for survival.


CONCLUSIONS
In the TAX327 trial, a PSA decline of > or = 30% within 3 months of chemotherapy initiation had the highest degree of surrogacy for overall survival, confirming data from the Southwest Oncology Group 9916 trial. However, given the wide CIs around the estimate of this moderate surrogate effect, overall survival should remain the preferred end point for phase III trials of cytotoxic agents in HRPC.
Armstrong
Andrew J
AJ
Duke Comprehensive Cancer Center, Durham, NC 27710, USA. andrew.armstrong@duke.edu
Garrett-Mayer
Elizabeth
E
Ou Yang
Yi-Chun
YC
Carducci
Michael A
MA
Tannock
Ian
I
de Wit
Ronald
R
Eisenberger
Mario
M
D000230:Adenocarcinoma / Q000175:diagnosis* / Q000188:drug therapy / Q000401:mortality / Q000556:secondary*; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000556:secondary*; D015897:Comorbidity; D000077143:Docetaxel; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008942:Mitoxantrone / Q000008:administration & dosage; D010146:Pain / Q000145:classification / Q000453:epidemiology / Q000517:prevention & control*; D010147:Pain Measurement; D011241:Prednisone / Q000008:administration & dosage; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage
D018931:Antineoplastic Agents, Hormonal; D043823:Taxoids; D000077143:Docetaxel; D008942:Mitoxantrone; D017430:Prostate-Specific Antigen; D011241:Prednisone