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

In this post-hoc analysis, we first assessed the PSA kinetic profile in AA plus prednisolone-treated mCRPC patients. There was a clear difference in the PSA kinetic profile between chemotherapy-naïve and chemotherapy-treated patients. The majority of chemotherapy-naïve patients showed a rapid PSA decline at week 4, and additional 4 months were needed to reach PSA nadir. On the other hand, the majority of chemotherapy-treated patients showed non-decline or 25 % elevation at week 4, and the mean time to reach PSA nadir was 2.0 months. Moreover, the percent change in the PSA values in chemotherapy-treated patients tended to be larger, and most of the patients experienced PSA progression within a year after treatment initiation (Fig. 1). The mean TTPP was approximately 4 months, which was approximately half of the value reported in JPN-201 (9.5 months). Differences in characteristics of patient populations with mCRPC may impact the PSA kinetic profile, and such PSA kinetic differences could mainly be associated with previous history of chemotherapy. The mechanisms related to the differences in PSA kinetic profiles between chemotherapy-naïve and chemotherapy-treated patients are unclear; however, it is recommended that PSA kinetics would be separately evaluated according to prior history of chemotherapy. Caffo et al. reported that the time to PSA nadir in responders among chemotherapy-treated mCRPC patients was 15.5 weeks with AA but 7.0 weeks with enzalutamide [12]. Moreover, the anti-tumor effects of both drugs are derived from different mechanisms of action; abiraterone inhibits androgen synthesis at non-gonadal sites (adrenal gland and intratumorally) to reduce androgens to below castrate concentrations, while enzalutamide, an anti-androgen, directly binds androgen receptors to inhibit androgen receptor nuclear translocation [17]. These differences in the mechanisms of action might affect PSA kinetics.

In the present study, some patients showed a continuous stable level of PSA (Fig. 1b). In JPN-201, of the 9 (19 %) patients categorized as non-decline, most did not show large PSA elevation within 12 months. The TTPP curves were similar between non-decline and 30 %-decline patients (Fig. 2a). Thus, for chemotherapy-naïve patients without PSA progression at week 4, there would be a clinically similar chance of benefit from AA treatment. This is also supported by the result of Cox regression analysis, HR was significant for PSA response (≥50 %) at week 12 but not for PSA decline (≥30 %) at week 4 (Table 3).

On the other hand, in JPN-202, the non-decline TTPP curve was shorter than that of 30 %-decline and differed from that of 25 %-elevation (Fig. 3a). A half of the non-decline patients had rapid PSA progression; however, another half of the patients showed continuous stable levels of PSA (Fig. 1d), suggesting that patients with non-decline still had some potential of obtaining a clinical benefit from the treatment. The TTPP curves based on PSA response at week 12 were close between responders and patients with non-progression (Fig. 3b). Overall, further observation is recommended for patients in both population regardless obtaining PSA elevation at week 4.

In addition, temporal PSA elevation was recently reported with docetaxel treatment [18], which led to the phenomenon being referred to as “PSA flare,” indicating a PSA elevation with initiation of an LHRH agonist. PSA flares were also reported with AA treatment [19, 20]. According to the definition by Olbert et al., wherein a PSA flare is defined as initially rising PSA under therapy, dropping thereafter to values below baseline, 3 of 9 non-decline patients (Fig. 1b; blue lines) in JPN-201and 1 of 21 in JPN-202 (Fig. 1d; blue lines) were considered to have a PSA flare. PSA transition in such patients showed slow PSA elevations for 2 months, which declined below baseline levels within 1 to 2 months after the peak level. In taxane-based chemotherapy, the pattern of flare-up was slightly different. In the chemotherapy-related PSA flare, a peak PSA level was reached within 1 month after the first dose, and peak PSA levels were detected 1 to 2 months earlier than in the present study [18, 21, 22].

In general, elevated or stable PSA levels are a key decision factor for treatment change in routine clinical practice. Based on the aforementioned results, careful consideration is recommended for evaluation of the efficacy and decision for treatment change in AA treatment.

Some limitations of the present study are as follows: TTPP is a well-known surrogate endpoint for OS and is easy to follow-up in clinical practice [8]. In the present study, investigation of OS was inappropriate because patient number and number of events were limited. Therefore, we alternatively evaluated TTPP. Nonetheless, the primary endpoint in both JPN-201 and JPN-202 was PSA response rate at week 12; however, patient number was insufficient to apply statistical testing to analyze TTPP between the subgroups. Especially, patient number of non-30 %-decline was limited (11 in chemotherapy-naïve and 25 in chemotherapy-treated population). Moreover, in clinical practice, a wide variety of prior therapies, patient conditions, and concomitant use of drugs may have a potential impact on PSA kinetic profiles; it will therefore be important to reconfirm these results in clinical practice.