Association of early PSA decline and time to PSA progression in abiraterone acetate-treated metastatic castration-resistant prostate cancer; a post-hoc analysis of Japanese phase 2 trials.
BACKGROUND
Previous studies have demonstrated an association between prostate-specific antigen (PSA) kinetics and predictive value for treatment outcomes. Abiraterone acetate (AA) is a newly approved cytochrome-P450C17 inhibitor for treatment of metastatic castration-resistant prostate cancer (mCRPC), and few studies have evaluated PSA kinetics using AA so far. Results of a study evaluating PSA kinetics in the beginning of AA and enzalutamide responded chemotherapy-treated patients suggested different trends between the drugs. PSA kinetics of AA-treated patients has been reported using large datasets; however, no studies which have fully evaluated PSA kinetics in the beginning treatment. The present study aimed to assess the PSA kinetics and relationship between the PSA kinetics and PSA progression in chemotherapy-naïve and chemotherapy-treated mCRPC patients receiving AA.


METHODS
We used two Japanese phase II trial datasets: JPN-201, chemotherapy-naïve mCRPC (n = 48) and JPN-202, chemotherapy-treated mCRPC (n = 46). PSA kinetic parameters were calculated using actual PSA values measured every 4 weeks, and a subgroup analysis was performed to evaluate the influence of early PSA response on time to PSA progression (TTPP). In addition, we used a Cox proportional hazard model to investigate the influence of variables on TTPP.


RESULTS
PSA declined from week 4 but took more time to achieve nadir. PSA kinetic parameters were different between the datasets, mean time to PSA nadir was 5.3 ± 5.6 and 2.0 ± 3.4 months, and TTPP was 9.5 ± 7.4 and 3.8 ± 4.8 months in JPN-201 and JPN-202, respectively. In the subgroup analysis of week 4 PSA decline status, Kaplan-Meier curves for TTPP were similar between early responders and non-progression patients in JPN-201 (median, 9.2 vs. 6.5 months, respectively) but separated in JPN-202 (median, 3.7 vs. 1.9 months, respectively). According to univariate Cox regression analysis, achievement of PSA response (≥50 %) at week 12 was associated with TTPP in the both trials, but the hazard ratio of PSA decline (≥30 %) at week 4 was not significant in JPN-201.


CONCLUSIONS
Our results suggest that PSA kinetics were not comparable and early PSA response showed different association to TTPP according to prior history of chemotherapy.


BACKGROUND
The original trials are registered at ClinicalTrials.gov. The identifiers are; JNJ-212082-JPN-201 , registered 20 December 2012 and JNJ-212082-JPN-202 , registered 30January 2013.
Medical Affairs Division, Janssen Pharmaceutical K.K., 5-2, Nishi-kanda, 3-Chome, Chiyoda-ku, Tokyo, 101-0065, Japan. mnakayam@its.jnj.com.
Masahiko
M
Nakayama
Medical Affairs Division, Janssen Pharmaceutical K.K., 5-2, Nishi-kanda, 3-Chome, Chiyoda-ku, Tokyo, 101-0065, Japan.
Hisanori
H
Kobayashi
Medical Affairs Division, Janssen Pharmaceutical K.K., 5-2, Nishi-kanda, 3-Chome, Chiyoda-ku, Tokyo, 101-0065, Japan.
Tomihiro
T
Takahara
Research and Development Division, Janssen Pharmaceutical K.K., 5-2, Nishi-kanda, 3-Chome, Chiyoda-ku, Tokyo, 101-0065, Japan.
Ryo
R
Oyama
Research and Development Division, Janssen Pharmaceutical K.K., 5-2, Nishi-kanda, 3-Chome, Chiyoda-ku, Tokyo, 101-0065, Japan.
Keiichiro
K
Imanaka
Medical Affairs Division, Janssen Pharmaceutical K.K., 5-2, Nishi-kanda, 3-Chome, Chiyoda-ku, Tokyo, 101-0065, Japan.
Kazutake
K
Yoshizawa
D000069501:Abiraterone Acetate / Q000627:therapeutic use*; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood; D018450:Disease Progression; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D017430:Prostate-Specific Antigen / Q000097:blood*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000098:blood supply* / Q000188:drug therapy* / Q000453:epidemiology; D015203:Reproducibility of Results; D012189:Retrospective Studies; D012307:Risk Factors; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D017430:Prostate-Specific Antigen; D000069501:Abiraterone Acetate
Abiraterone acetate; Castration-resistant prostate cancer; Cox proportional hazard model; Kinetics; Prostate-specific antigen