Change in PSA velocity is a predictor of overall survival in men with biochemically-recurrent prostate cancer treated with nonhormonal agents: combined analysis of four phase-2 trials.
BACKGROUND
Multiple phase-2 trials in men with biochemically-recurrent prostate cancer (BRPC) have assessed the impact of nonhormonal agents on PSA kinetics. We have previously demonstrated that changes in PSA kinetics correlate with metastasis-free survival; however, it is unknown whether these changes also correlate with overall survival (OS).


METHODS
We performed a combined retrospective analysis of 146 men with BRPC treated on phase-2 trials using one of four investigational drugs: lenalidomide (n=60), marimastat (n=39), ATN-224 (n=22) and imatinib (n=25). We examined factors influencing OS, including within-subject changes in PSA kinetics (PSA slope, PSA doubling time and PSA velocity), before and 6 months after treatment initiation.


RESULTS
After a median follow-up of 83.1 months, 49 of 146 men had died. In univariate Cox regression analysis, two factors were associated with OS: baseline PSA velocity and change in PSA velocity on therapy. In a landmark multivariable model, stratified by study (which controlled for age, Gleason score, type of local therapy and use of androgen-deprivation therapy prior to metastases), baseline PSA velocity and increase in PSA velocity on therapy remained independent predictors of OS. Median OS for men with an increase in PSA velocity on treatment was 115.4 months and was not reached for men with a decrease in PSA velocity (hazard ratio=0.47, 95% confidence interval 0.25-0.88; P=0.02).


CONCLUSIONS
This hypothesis-generating study suggests that within-subject changes in PSA velocity after initiation of nonhormonal therapy may correlate with OS in men with BRPC. If validated in prospective trials, change in PSA velocity may represent a reasonable intermediate end point for screening new agents in these patients.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
D L
DL
Suzman
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
X C
XC
Zhou
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
M L
ML
Zahurak
Kimmel Cancer Center at Thomas Jefferson University Hospital, Philadelphia, PA, USA.
J
J
Lin
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
E S
ES
Antonarakis
D000368:Aged; D001549:Benzamides / Q000008:administration & dosage; D015415:Biomarkers; D014408:Biomarkers, Tumor / Q000097:blood*; D018572:Disease-Free Survival; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D000068877:Imatinib Mesylate; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000097:blood* / Q000453:epidemiology / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery; D011743:Pyrimidines / Q000008:administration & dosage
D001549:Benzamides; D015415:Biomarkers; D014408:Biomarkers, Tumor; D006877:Hydroxamic Acids; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C100342:marimastat; D017430:Prostate-Specific Antigen