Health-related quality of life with enzalutamide versus flutamide in castration-resistant prostate cancer from the AFTERCAB study

According to GLOBOCAN 2020, prostate cancer (PC) is the second most frequently diagnosed cancer and fifth leading cause of cancer-related death among men, with an estimated 1.4 million new cases [1]. In Japan, PC was reported as the most common cancer in men in 2021, with an incidence of 95,400 persons per year, and the sixth most common cause of cancer-related deaths [2]. Androgen deprivation therapy (ADT) via medical or surgical castration using luteinizing hormone-releasing hormone agonists/antagonists (LHRHas) with or without antiandrogen drugs has remained the mainstay of treatment for PC for decades [3, 4]. Combined androgen blockade (CAB) therapy of bicalutamide and ADT is commonly used to treat PC in Japan [5‐7]. Though ADT offers near certain remission, cancer cells become resistant to ADT, leading to disease reactivation and transition to a lethal phenotype—castration-resistant PC (CRPC) [8]. The Japanese Urological Association’s 2012 PC guidelines recommend alternative androgen therapy (AAT) with flutamide plus ADT for the treatment of patients with CRPC who progress despite CAB [9]. Recently developed new agents, including hormonal therapy, such as enzalutamide, have significantly transformed CRPC management, increasing overall survival and quality of life (QoL) [4].

Enzalutamide is a targeted oral androgen receptor (AR) inhibitor that binds competitively to the ligand-binding domain of the AR, thus inhibiting nuclear translocation of the AR, DNA binding, and coactivator recruitment [10]. Its clinical activities have been well established in phase 3 randomized clinical trials [11‐15]. Japan’s Ministry of Health, Labour and Welfare approved enzalutamide for the treatment of men with CRPC in 2014 [16] and recently amended the indication to include metastatic hormone-sensitive PC and PC with distant metastasis, based on the ARCHES (NCT02677896) [15] and ENZAMET (NCT02446405) trials [17].

With the evolving therapeutic landscape and the need for long-term therapy, the potential impact of adverse effects on patients’ health-related QoL (HRQoL) is a pressing challenge for clinicians treating PC [18]. Cancer-related fatigue, a multifaceted concept comprising the physical, social, emotional, and psychological symptoms that patients undergoing cancer treatment experience, is commonly reported among men with PC [19‐22]. The Erim et al. study reported that PC-related anxiety had notable associations with low mood/nervousness, productivity loss, and risk of probable depression, impacting patients’ HRQoL [23]. Novel hormonal therapy has a different spectrum of adverse events (AEs) that may impact HRQoL [14]. In phase 3 trials, AEs such as hot flash, fatigue, arthralgia, hypertension, increased weight, and diarrhea were observed with enzalutamide; however, it achieved a favorable safety profile overall, with no unexpected AEs and fewer reported ≥ grade 3 AEs [15]. Although the oncological benefits for a plethora of new agents have been studied, the associated HRQoL evidence is scarce. HRQoL for patients with PC comprises specific urological-related symptoms and overall HRQoL. The currently used validated questionnaires to measure HRQoL for a patient with PC include, but are not limited to, the Functional Assessment of Cancer Therapy–Prostate (FACT-P) [24], EuroQoL 5-Dimension 5-Level instruments (EQ-5D-5L) [25], Brief Pain Inventory–Short Form (BPI-SF) [26], and Brief Fatigue Inventory (BFI) [27].

A previous publication from the AFTERCAB (NCT02918968) study conducted in Japanese patients with CRPC who failed CAB therapy with bicalutamide compared the efficacy and safety of enzalutamide plus ADT and flutamide plus ADT. The time to prostate-specific antigen (PSA) progression was significantly extended by enzalutamide compared to flutamide, while both therapies had acceptable safety profiles [9]. This post hoc analysis of the AFTERCAB study determined the HRQoL benefit of enzalutamide plus ADT therapy compared to flutamide plus ADT for the treatment of patients with CRPC. The change in HRQoL was assessed through four patient-reported outcome (PRO) measures—FACT-P, EQ-5D-5L, BFI, and BPI-SF using the existing data set of the AFTERCAB study.

Overall, 253 patients were enrolled in the study, 47 of whom discontinued prior to randomization. The remaining 206 patients were randomized to an enzalutamide (n = 102) or flutamide (n = 104) group.

This post hoc analysis of the AFTERCAB study assessed the benefit of enzalutamide plus ADT compared to flutamide plus ADT assessed by PRO measures in Japanese patients with CRPC. Overall, the HRQoL between the enzalutamide and flutamide groups was not statistically different during first-line treatment among all PRO measures, longitudinal change from baseline, proportion of HRQoL deterioration, and time to HRQoL deterioration measured by the FACT-P, EQ-5D-5L, BPI-SF, and BFI global score. The plausible rationale for the similarity in HRQoL between the two treatment groups during first-line treatment may be because the recruited patients had relatively early phase CRPC with limited impact on HRQoL. In addition, since the treatment switch decision to second-line was made based on PSA progression, the general health condition of patients was maintained at the end of first-line treatment without significant deterioration in PRO.

Currently, limited evidence on QoL outcomes is available in Japanese patients with PC [29]. The Arai et al. study that assessed HRQoL in 203 Japanese patients with PC concluded that the maximum androgen blockade (MAB) with bicalutamide plus LHRHas did not reduce overall QoL, though the MAB was superior to monotherapy in achieving early improvement of QoL related to micturition disorder and pain [29]. Previous studies assessing the effect of enzalutamide on HRQoL in randomized phase 3 trials demonstrated improved HRQoL versus placebo, confirming that the addition of enzalutamide allowed patients to maintain their HRQoL [30‐33]. In the Cella et al. analyses of longitudinal changes in FACT-P scores in the AFFIRM trial, mean FACT-P score decreased 1.52 points with enzalutamide compared to 13.73 points with placebo (p < 0.001) after 25 weeks. Significant treatment differences favoring enzalutamide were observed for all FACT-P subscales [30]. In a randomized phase 3 trial assessing HRQoL in men with nonmetastatic CRPC, enzalutamide showed a clinical benefit by delaying pain progression, symptom worsening, and decrease in functional status compared with placebo [33]. These results are consistent with this study in which enzalutamide exhibited a significantly extended time to PSA progression, with no significant change in HRQoL compared to flutamide during the treatment period. Enzalutamide may be a valuable addition to the treatment armamentarium of PC in Japan, as shown by previous study results validating its efficacy and safety. In the Iguchi et al. study, the 3 month (80.8% versus 35.3%) and 6 month (73.1% versus 31.4%) PSA response rates were significantly higher in patients receiving enzalutamide compared to flutamide, respectively [34]. These study results corroborate the benefits previously published from the AFTERCAB study from a patient’s perspective. Results from the AFTERCAB study assessing the efficacy and safety of enzalutamide also showed improvement in ≥ 50% PSA response rate with first-line therapy (72.5% for enzalutamide first versus 34.6% for flutamide first) [9].

Although this study is a preliminary analysis demonstrating the comparison of enzalutamide and flutamide by changes in HRQoL in Japanese patients with CRPC, the study results must be interpreted with caution. This open-label study did not investigate overall or cancer-specific survival. Various statistical methods are available to analyze longitudinal data and assess missing data. The MMRM method assumes that the missing data follow the pattern of patients remaining in the study. Though the analysis window for MMRM in the study was up to week 61 to remove biases introduced by missing data, the results of the MMRM analysis should be interpreted with caution due to a substantial amount of missing data, especially in the flutamide group. A PMM analysis with delta-adjusted MI showed results consistent with MMRM. Moreover, these results were derived from a post hoc analysis that was not initially designed for the comparison of PROs; hence, it was unlikely to demonstrate statistical significance. As an additional limitation of the crossover study design, the study treatment was switched to other upon PSA progression, making it difficult to interpret results. Despite these limitations, the study presents vital findings related to HRQoL outcomes that are beneficial to further inform the use of enzalutamide in Japan.

The study demonstrated that similar HRQoL deterioration based on MID criteria between the enzalutamide and flutamide groups’ changes in HRQoL were stable, and no significant change from baseline to week 61 was observed in either group. Enzalutamide, therefore, significantly extended time to PSA progression compared to flutamide, with no significant change in HRQoL during the enzalutamide treatment period.