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

BMC Urology, Jun 2016

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. Trial registration 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.

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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

Nakayama et al. BMC Urology 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 Masahiko Nakayama 1 Hisanori Kobayashi 1 Tomihiro Takahara 1 Ryo Oyama 0 Keiichiro Imanaka 0 Kazutake Yoshizawa 1 0 Research and Development Division, Janssen Pharmaceutical K.K. , 5-2, Nishi-kanda, 3-Chome, Chiyoda-ku, Tokyo 101-0065 , Japan 1 Medical Affairs Division, Janssen Pharmaceutical K.K. , 5-2, Nishi-kanda, 3-Chome, Chiyoda-ku, Tokyo 101-0065 , Japan 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. Trial registration: 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. Abiraterone acetate; Castration-resistant prostate cancer; Kinetics; Prostate-specific antigen; Cox proportional hazard model Background Globally, the estimated incidence of prostate cancer was approximately 1.4 million in 2013. There was a 3-fold increase in this incidence from 1990 to 2013, together with aging and population growth [ 1 ]. Since Huggins et al. discovered that prostate cancer growth is stimulated by androgens, castration has been the mainstay of advanced-stage prostate cancer treatment [ 2 ]; however, most patients develop resistance to castration. Abiraterone acetate (AA) is a prodrug of abiraterone, which is a first-in-class inhibitor of cytochromeP450C17 that plays a role in the mechanism of castration resistance by de novo androgen synthesis [ 3 ]. It is approved with prednisone for treatment of metastatic castration-resistant prostate cancer (mCRPC) worldwide. AA plus prednisone significantly prolonged overall survival (OS) compared with placebo plus prednisone for treatment of chemotherapy-naïve and chemotherapy-treated mCRPC in pivotal global trials [ 4, 5 ]. In Japan, two singlearm, open-label, phase II trials were separately conducted for the purpose of obtaining local registration [ 6, 7 ]. Prostate-specific antigen (PSA) is a reliable, sensitive, and easy to measure biomarker for prostate cancer and is therefore widely used for evaluation of treatment in practice [ 8, 9 ]. PSA kinetics has been studied in androgen deprivation therapy using anti-androgens or taxanes to analyze its predictive value for time-dependent outcomes such as OS and disease progression. Several studies have reported strength of PSA decline and its predictive value for OS, although certain results were controversial [ 9–11 ]. Recently, Caffo et al. reported the PSA kinetics of AA and enzalutamide responders and demonstrated different trends with regard to PSA kinetics betwee (...truncated)


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Masahiko Nakayama, Hisanori Kobayashi, Tomihiro Takahara, Ryo Oyama, Keiichiro Imanaka, Kazutake Yoshizawa. 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, BMC Urology, 2016, pp. 27, 16, DOI: 10.1186/s12894-016-0148-4