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Impact of alternative antiandrogen therapy for Japanese prostate cancer patients in the era of new hormonal therapy

DOI: 10.1111/iju.14135 After new hormonal therapies, such as abiraterone and enzalutamide, which were approved in Japan in 2014, were introduced, AA therapy fell out of favor worldwide. AA therapy, a grade B recommendation in the 2012 Japanese Clinical Practice Guidelines, was not listed in the 2016 Guidelines per the world trend. However, sensitivity to hormonal therapy is higher in Japanese patients than in Caucasian patients, and AA therapy is still considered useful in the era of new hormonal therapy. We evaluated the prognostic significance of AA therapy, and compared PSA response rates for abiraterone and enzalutamide between responders and non-responders to AA therapy. Between 2001 and 2015, 141 patients with advanced PC who underwent AA therapy with flutamide after failure of initial maximum androgen blockade with bicalutamide in Osaka Rosai Hospital, Sakai, Osaka, Japan, were retrospectively reviewed. Data collected included age; clinical T, N and M stages; biopsy GS; initial serum PSA value; LDH, ALP and hemoglobin concentrations; time to CRPC; presence of PSA decline with AA therapy; use of new hormonal therapy; and follow-up data. Prognostic outcomes and these 12 factors were analyzed. Statistical analyses were carried out using JMP 14 (SAS Institute, Cary, NC, USA). Patient characteristics are summarized in Table S1. The median follow-up duration was 57 months (range 7–191 months), and the estimated 5-year OS was 64.7%. Overall, 73 (51.8%) patients died, with 56 (39.7%) dying of PC. After introduction of AA therapy, the numbers of patients achieving PSA decline >50%, 0–50% and unchanged elevation of PSA were 43 (30.5%), 37 (26.2%) and 61 (43.3%), respectively. Of the 141 patients, 50 received abiraterone or enzalutamide, and PSA decline occurred in 41 patients (82.0%). Kaplan–Meyer analysis and log–rank tests showed that 61 patients not experiencing PSA decline with AA therapy had significantly poorer OS than 43 and 37 patients showing PSA decline >50% and 0–50%, whereas solely between the patients showing PSA decline >50% and 0–50%, no significant difference was observed (Fig. 1a). Thereafter, we divided these patients into two groups, responders (n = 80) and non-responders (n = 61), for further study. We confirmed that OS was significantly better in responders versus non-responders (P = 0.0011; Fig. 1b) and in new hormone users versus non-users (P < 0.001; Fig. 1c). The association of the 12 factors with OS was evaluated with univariate and multivariate Cox proportional hazards analyses. Univariate analysis showed age, LDH, ALP, time to CRPC, response to AA therapy and use of abiraterone or enzalutamide to be significantly associated with OS. Multivariate analysis showed that time to CRPC, response to AA therapy and use of abiraterone or enzalutamide were independent risk factors for OS (Table S2). Except for biopsy GS, no factors were associated with PSA decline after AA therapy (Table S3). Furthermore, PSA decline with abiraterone or enzalutamide was observed significantly more frequently (P = 0.0225) in responders (25/28, 92.86%) after AA therapy than in non-responders (15/22, 68.18%; Fig. 1d) and resulted in better prognosis (Fig. S1). In summary, AA therapy was effective in 56.7% of patients, and these responders had significantly better OS than non-responders, similar to previous studies. Furthermore, cross-resistance between AA therapy and new hormonal therapy was not detected, showing that compared with non-responders, responders to AA therapy still have hormonal sensitivity and can expect an effect from new hormonal therapy. Recently, as one cause of drug resistance, various AR mutations were reported to rise during antihormone treatments, and AR mutation points differ between bicalutamide, flutamide, abiraterone and enzalutamide because, as our study showed, cross-resistance between AA therapy and new hormonal therapy is non-existent. To our knowledge, this is the first report to show that AA therapy does not reduce efficacy after new hormonal therapy. Furthermore, new hormonal therapy resulted in reduced effectiveness and poorer prognosis in non-responders to AA therapy, showing that these patients might derive potential benefit from chemotherapy rather than abiraterone or enzalutamide. These findings show that AA therapy might still be of therapeutic value in Japanese patients with advanced PC in the era of new hormonal therapy. However, the present study