Comparing Enzalutamide and Flutamide as First-Line Androgen Therapy for Japanese Men with Castration-Resistant Prostate Cancer: A Clinical Study

In 2018, the estimated incidence of prostate cancer was high, with Japan accounting for 6% (78,400 people) of the total global incidence (1,276,106 people), ranking it sixth in cancer-related mortality (12,400 deaths). Combined androgen blockade (CAB), which combines nonsteroidal antiandrogen with Androgen Deprivation Therapy (ADT), stands as the gold standard in prostate cancer treatment. Initially, Bicalutamide emerged as one of the first nonsteroidal antiandrogens used in this approach. Nevertheless, some patients experience prostate-specific antigen (PSA) recurrence and progress to castration-resistant prostate cancer (CRPC). Hence, alternative androgen therapies (AAT) replacing bicalutamide with either flutamide or enzalutamide have been considered.

Based on the Japanese Urological Association 2012 Prostate Cancer Guidelines, flutamide + ADT, was the recommended alternative androgen therapy. Nevertheless, the PSA benefit observed in some patients was modest requiring additional AAT options such as enzalutamide. Enzalutamide is a potent oral androgen receptor inhibitor approved in some countries for treating men with metastatic hormone-sensitive prostate cancer and CRPC, irrespective of metastases. Other countries have it under regulatory consideration for approval.
A randomized, open-label, Phase 4, post-marketing clinical study, AFTERCAB, was conducted to compare the efficacy and safety of (enzalutamide + ADT) and (flutamide + ADT) in Japanese men with metastatic or nonmetastatic CRPC who progressed despite receiving the CAB with bicalutamide + ADT. In this study, patients were randomized in a 1:1 ratio to enzalutamide + ADT (enzalutamide first) or flutamide + ADT (flutamide first) as first-line therapy. Enzalutamide was administered at 160mg/day and flutamide at 375mg/day (125mg three times daily).
The number of patients screened was 253, of which only 206 were randomized, with 102 patients assigned to enzalutamide first and 104 to flutamide first. Randomization was stratified to study site and disease stage. Afterwards, patients were subjected to efficacy and safety analyses. Some patients discontinued the treatment in either the first or the second-line therapy.
The primary endpoint was the time from randomization to the date of PSA progression with first-line therapy (TTPP1). For men with PSA decline at week 13, PSA progression was defined as ≥ 25% increase and an absolute increase of ≥ 2 ng/ml above the nadir, confirmed by a second consecutive value ≥ three weeks later. For men without PSA decline at Week 13, PSA progression was defined as ≥25% increase and an absolute increase of ≥2 ng/ml above baseline.

The secondary endpoints were:
· The total time to PSA progression with first-line therapy + second-line therapy (TTPP2),
· PSA response rate (≥50% or ≥90%) with first line-therapy,
· PSA response rate (≥50% or ≥90%) with first line-therapy at week 13,
· Time to 50% PSA reduction with first-line therapy,
· Time to treatment failure with first-line therapy (TTF1),
· Time to treatment failure with second-line therapy (TTF2), and
· Radiographic progression-free survival (rPFS).
Enzalutamide + ADT as first-line AAT resulted in a significant improvement in TTPP1 versus flutamide + ADT. Median TTPP1 with a 95% confidence interval was 21.4 months with enzalutamide versus 5.8 months with flutamide.
As for the secondary endpoint, median TTPP2 was longer with enzalutamide first (35.9 months) compared to flutamide first (21.2 months). Moreover, 72.5% of men receiving enzalutamide first and 34.6% receiving flutamide first had ≥50% PSA response. Corresponding values of ≥90% PSA response were 54.9% and 16.3%, respectively. Furthermore, the time to 50% PSA reduction with first-line therapy (95% CI) was significantly shorter for enzalutamide first, compared with flutamide first: 2.8 months compared with 5.6 months. Also, the TTF1 was remarkably longer with enzalutamide first (13.8 months) compared to flutamide first (4.6 months). TTF2 was not significantly longer in the enzalutamide first group (23.0 months) compared to the flutamide first group (16.6 months). Lastly, no significant difference was observed in rPFS between men with distant metastases receiving enzalutamide first and those receiving flutamide first.
Adverse events (AEs) were monitored throughout the treatment period up until 28 days after the final dose of the study drug. The incidence of AEs was higher in men receiving enzalutamide first, where the most reported AE with first-line therapy was nasopharyngitis. Nevertheless, the greater TTF1 and TTF2 values and longer treatment exposure indicate that patients spent longer on enzalutamide as both first- and second-line therapies, confirming the overall benefit of enzalutamide.
Overall, the results of this study confirm that as a first-line AAT, enzalutamide + ADT, compared to flutamide + ADT, provided significant improvement in time to PSA progression and other PSA-related outcomes. These findings were consistent with the previously published OCUU-CRPC study. Therefore, for Japanese men with metastatic or nonmetastatic CRPC that progress despite CAB with bicalutamide + ADT, (enzalutamide+ ADT) may be the preferred treatment option.