Background
Prostate cancer is the most commonly diagnosed cancer and the third leading cause of cancer-related death among men worldwide [
1]. In most patients who are treated for advanced recurrent prostate cancer with androgen-deprivation therapy (ADT) that comprise a luteinizing hormone-releasing hormone (LHRH) analogue or orchiectomy with or without an anti-androgen, disease progression occurs despite effective suppression of serum testosterone. These patients are then diagnosed with castration-resistant prostate cancer (CRPC).
In Japan, ADT has been widely used not only for advanced recurrent prostate cancer, but also for localized prostate cancer in elderly patients. Although ADT is effective only for a certain period and causes recurrence as CRPC, several patients actually respond to treatment for long periods [
2]. Combined androgen blockade (CAB) therapy using an LHRH analogue with an anti-androgen is superior to ADT without an anti-androgen in terms of long-term efficacy among Japanese patients with prostate cancer [
3]. Despite some disadvantages of CAB such as higher cost compared to ADT without anti-androgen, an observational study that compared CAB and castration showed good prognosis in patients with T1c-T3 prostate cancer [
4]. At present, CAB using bicalutamide is more widely used in Japan than LHRH analogue monotherapy, and many elderly patients with localized prostate cancer are treated with CAB.
However, a proportion of patients with prostate cancer who are treated with CAB experience prostate-specific antigen (PSA) recurrence and are diagnosed as CRPC after confirming for anti-androgen withdrawal syndrome (AWS). Alternative anti-androgen therapy (AAT) with flutamide as the subsequent therapy after CAB therapy with bicalutamide is widely used before the androgen receptor targeted therapy (ART) era, particularly in Japan [
5‐
11]. The response rate of AAT, defined as a decrease of > 50% from the baseline serum PSA level, was 22%, and patients who respond to AAT have been reported to have good prognosis [
6]. This phenomenon is attributed to the different mechanism of actions among anti-androgens [
9].
Flutamide, a non-steroidal oral anti-androgen, was often used in clinical practice before bicalutamide was approved. Some small, single-arm non-randomized studies suggest a PSA benefit in flutamide as second-line hormonal therapy [
5‐
11]. However, the use of flutamide is optional for limited patients with CRPC according to the American Urological Association guidelines [
12] owing to the modest PSA benefit, with PSA declines of > 50% occurring typically in only 20–40% of men with a median duration measured in several months.
Enzalutamide is an androgen receptor inhibitor that targets several steps in the androgen receptor signaling pathway. It inhibits binding of androgens to the androgen receptor, androgen-receptor nuclear translocation, and androgen receptor-mediated DNA binding [
13]. In preclinical studies, enzalutamide showed a higher affinity for the androgen receptor and superior suppression of key components of the androgen receptor signaling pathway than bicalutamide [
13,
14]. Subsequently, enzalutamide was approved for the treatment of metastatic CRPC based on the results of two pivotal placebo-controlled phase III trials, namely, AFFIRM [
15] and PREVAIL [
16].
Before the ART era, the treatment options for CRPC are limited, and AAT with flutamide has been widely used in Japan. However, no clinical studies compared AAT with flutamide and enzalutamide as treatment modalities for CRPC. Creating clinical evidence of the superiority of enzalutamide to AAT (bicalutamide to flutamide) in the post-AWS setting in terms of safety and efficacy would be meaningful. To the best of our knowledge, the OCUU-CRPC study is the first randomized head-to-head trial of enzalutamide versus flutamide in patients with CRPC after CAB therapy with bicalutamide.
Discussion
In the PREVAIL study, enzalutamide significantly reduced the risk of radiographic progression and death by 81% (HR: 0.19;
P < 0.0001) and 29% (HR 0.71,
P < 0.0001), respectively, compared with a placebo in chemo-naive men with metastatic CRPC [
16]. In this study, 61 Japanese were enrolled (enzalutamide,
N = 28; placebo,
N = 33), and most them received more than two types of anti-androgens prior to enrollment, including bicalutamide and flutamide. Even after bicalutamide and flutamide, 17 patients (60.7%) had confirmed PSA responses (≥50% reduction from baseline), and enzalutamide reduced the risk of death by 41% (HR: 0.59; 95% CI: 0.20–1.78) [
18]. Japanese patients reported less baseline pain, had less soft-tissue disease, and had lower median PSA at baseline. ADT is more widely used as an initial treatment for early stages of prostate cancer in Japan than in other countries [
19]. Before the ART era, the treatment options for CRPC were limited, and AAT with flutamide has been widely used in Japan. Even after enzalutamide and abiraterone were introduced, Bic-CAB as primary therapy and AAT with flutamide as the subsequent therapy for advanced prostate cancer were commonly used in Japan.
In the OCUU-CRPC study, we compare the efficacy and safety of enzalutamide and AAT with flutamide in patients with CRPC who were previously treated with CAB therapy with bicalutamide. Because enzalutamide was superior to bicalutamide in terms of PSA response in patients with CRPC who did not receive any prior bicalutamide or chemotherapy in the TERRAIN and STRIVE studies [
20,
21], the expected result of the primary endpoint of OCUU-CRPC study will be that enzalutamide is superior to flutamide in terms of PSA response. A longer time to disease progression with enzalutamide than bicalutamide or flutamide may translate to better overall survival, and enzalutamide may be more effective for men with low-volume disease according to post hoc analysis of the PREVAIL trial [
22]. However, AAT with flutamide was particularly effective for patients with CRPC who had long response duration to Bic-CAB [
8], and the effect of enzalutamide after AAT with flutamide was preserved [
18]. Because enzalutamide and flutamide costs $2478 and $208 ($118 if generic drug) per month in Japan, respectively, AAT with flutamide may be more beneficial and accessible for limited patients owing to its lower cost.
The OCUU-CRPC study has some limitations. The PSA response rate at 3 months without radiographic examinations as the primary endpoint may not be associated directly with overall survival. Moreover, this is not a crossover trial and the treatment after enzalutamide and flutamide is not defined by the protocol. Additionally, because the patients included in this study are Japanese and because flutamide is not commonly used for CRPC in other countries, the findings of the OCUU-CRPC study cannot be generalized and applied to patient populations in other locations or regions.
Currently, a similar clinical trial with enzalutamide and flutamide for CRPC (NCT02918968) is undergoing in Japan, in which the primary endpoint is time to PSA progression with first-line therapy. The result of the NCT02918968 will be published a few years after our result.
Acknowledgements
The following individuals and institutions participated in OCUU-CRPC study: K. Kuratsukuri, N. Kuwabara, T. Iwai, Osaka City University, Osaka, Japan; T. Ohmachi, Bellland General Hospital, Sakai, Japan; K. Harimoto, C. Masuda, Y. Kuroki, Fuchu Hospital, Izumi, Japan; S. Yamamoto, Ikuwakai Memorial Hospital, Osaka, Japan; Y. Yamakoshi, Ishikiriseiki Hospital, Higashi-osaka, Japan; H. Iwata, K. Uemiya, Itami Municipal Hospital, Itami, Japan; K. Tashiro, Meijibashi Hospital, Matsubara, Japan; Y. Takegaki, Minamiosaka Hospital, Osaka, Japan; M. Yoshimoto, S. Sugita, Ohno Memorial Hospital, Osaka, Japan; T. Sugimoto, W. Sakamoto, K. Ishii, Osaka City General Hospital, Osaka, Japan; T. Adachi, C. Nishihara, Osaka City Juso Hospital, Osaka, Japan; Y. Yoneda, Y. Komemushi, Osaka General Hospital of West Japan Railway Company, Osaka, Japan; T. Ito, T. Sonoda, T. Deguchi, PL Hospital, Tondabayashi, Japan; S. Tanabe, M. Mitsuhashi, Shirasagi Hospital, Osaka, Japan; N. Kumada, J. Matsuda, T. Hase Suita Municipal Hospital, Suita, Japan; S. Ikemoto, M. Kamizuru, Y. Machida, Yao Municipal Hospital, Yao, Japan; H. Iimori, T. Kanamaru, Yao Tokushukai General Hospital, Yao, Japan.