Using an anchored MAIC, the present study indirectly compared tolerability and HRQoL among men with high-risk nmCRPC who, in the framework of two independent clinical studies, received apalutamide (SPARTAN) and enzalutamide (PROSPER). The probabilities of apalutamide having a more improved tolerability profile as evidenced by the reduced occurrence of several specific AEs, including fatigue, decreased appetite, hypertension, and fall, versus enzalutamide exceeded 90%. Additionally, this MAIC demonstrated, with high probability, that apalutamide had a more favorable tolerability as defined by reduced occurrence of any AE (66.9% probability) or a reduced occurrence of SAEs (90.9% probability) than enzalutamide. The probability of a better HRQoL measured based on a change in the FACT-P total score was 73.1% with apalutamide versus enzalutamide. The probabilities of a more favorable change in all FACT-P subscale scores with apalutamide versus enzalutamide were also pronounced. Taken together, these results suggest that men with nmCRPC treated with apalutamide are more likely to experience fewer AEs and better HRQoL than men treated with enzalutamide.
In the present study, the probability of fewer AEs (any) with apalutamide relative to enzalutamide reached 66.9%. This probability was higher for SAEs (90.9%). This is notable because the study design of SPARTAN allowed for more frequent AE reporting (every 4 weeks) than in PROSPER (every 16 weeks). Despite the more frequent collection of AE events in SPARTAN, which would theoretically increase the probability of detecting more AEs, the results of this study support higher probability of overall lower AEs with apalutamide treatment, suggesting that the tolerability profile of apalutamide could be better than enzalutamide. With regard to the individual AEs assessed, fatigue was most differentiated between apalutamide and enzalutamide. Management of fatigue may be an important factor for overall treatment success in patients with advanced prostate cancer. For example, in the PREVAIL study of enzalutamide in metastatic CRPC, fatigue was the most common AE leading to treatment discontinuation [35]. Although additional research is needed to validate the relationship of fatigue-related treatment discontinuation in nmCRPC, the observation in this study of a higher probability of reduced fatigue observed with apalutamide versus enzalutamide could be an important consideration for treatment optimization.
Another noteworthy observation was the high probability of reduced occurrence of dizziness and falls among apalutamide users compared with enzalutamide users. These two AEs are likely associated with an increased risk of accidental fracture. While both agents delay pathologic fractures secondary to metastases through their antitumor activity [1, 2], they are used concomitantly with ADT, which is known to be associated with bone mineral density loss and increased risk of accidental fracture [36]. Therefore, the high probability of reduced occurrence of dizziness and falls with apalutamide relative to enzalutamide may also lead to a reduced incidence of accidental fractures. In contrast, the higher probability of occurrence of diarrhea with apalutamide versus enzalutamide might be related to differences in the formulation of the two agents. At the start of the SPARTAN study, patients were initiated on an apalutamide formulation in soft-gel capsules, but these were subsequently changed to tablets after a protocol amendment. Data collected from the SPARTAN study indicate that patients receiving capsules experienced more AEs, including GI-related AEs, than patients receiving tablets. Given that excipients may cause gastrointestinal side effects, it is unclear how the initial formulation of apalutamide affected the incidence of diarrhea.
Saad et al. recently published the results of a prespecified exploratory analysis of HRQoL in SPARTAN, that was assessed with FACT-P [23]. In the analysis of time to deterioration of the FACT-P score, there was no difference between the study arms based on the CIs. When evaluating LS mean changes during follow-up versus baseline, a deterioration of HRQoL was numerically more apparent in the ADT arm than in the apalutamide arm. In PROSPER, discrepancies in the time to FACT-P deterioration exist between the unconfirmed and confirmed (i.e., deterioration confirmed at the next consecutive visit) analyses [1, 24]. In the confirmed analysis, a significantly less rapid deterioration was observed in the enzalutamide arm compared with the ADT arm [24]. In terms of the LS mean changes in the FACT-P score during follow-up versus baseline, a numerical but not statistical advantage was observed for the enzalutamide arm in PROSPER [24]. Through an anchored MAIC of HRQoL between the apalutamide and enzalutamide arms of SPARTAN and PROSPER, the present study complemented the findings from the two studies, suggesting that apalutamide may provide additional HRQoL benefits relative to enzalutamide.
The present study has many strengths. The Bayesian MAIC approach used here accounts for differences in measured baseline characteristics in contrast to a previous indirect comparison of apalutamide and enzalutamide conducted by Wallis et al., which did not adjust for baseline characteristics [13]. The Bayesian MAIC approach is different from the Bucher technique used by Wallis et al. and Nieto-Gomez et al. [12, 14], with the latter likely to produce more biased estimates when key baseline characteristics differ (e.g., PSADT) [37]. Furthermore, the probabilistic interpretation of the Bayesian approach enables stating the extent to which a hypothesis is true or false. For instance, in the current study, there was an 89.6% probability of reduced occurrence of SAEs with apalutamide versus enzalutamide in nmCRPC patients. This approach is more relevant for clinical and reimbursement decision-making than the classic frequentist approach, which dichotomizes results to be either significant or non-significant, based on the chosen significance threshold, and does not indicate the probability of the hypothesis being true or false [37]. Moreover, the analyses presented here provide a high level of granularity on AEs and HRQoL, with multiple individual AEs analyzed as well as multiple subscales and composite scores of the FACT-P. Since the value of different aspects of HRQoL and AEs may vary among individual patients (e.g., due to existing comorbidities), the granularity of the analysis may be especially useful in clinical decision-making. As nmCRPC patients are largely asymptomatic, limiting the burden of any treatment while maximizing HRQoL benefit is of clinical relevance when initiating a treatment for these patients, especially since treatment duration might extend over multiple years.
The present study is subject to some limitations. Although potential for biases was substantially reduced after matching, unobserved or unmeasured confounders may impact the relative effect of treatments on the outcomes of interest. Both studies are ongoing, and further analyses will be needed to confirm the potential advantages of apalutamide versus enzalutamide with respect to tolerability and long-term health effects, including HRQoL, over significantly longer follow-up periods. The analyses performed to compare AEs used data from the ITT population because of the unavailability of baseline characteristics for patients in the safety population. However, in both studies, the sizes of the safety and ITT populations differed only slightly, suggesting that any differences in baseline characteristics between the two populations should be minimal. It is important to note that AEs of interest were only analyzed if reported in both studies. For example, rash (apalutamide arm: 23.8%; ADT arm: 5.5%), hypothyroidism (apalutamide arm: 8.1%; ADT arm: 2.0%), and seizures (apalutamide arm: 0.2%; ADT arm: 0) were only assessed in SPARTAN and were therefore not included in the current analysis. More specifically, a post hoc analysis of the SPARTAN study in patients with and without rash was conducted. The median start and stop times of reported rash were evaluated and compared with FACT-P and EuroQol 5 dimension (EQ-5D) scores to get a sense of the impact of rash on HRQoL. No differences were observed between groups. In addition, even though short-term (≤ 4 weeks) administration of corticosteroids was permitted in SPARTAN, the extent of their use in PROSPER was not known. Moreover, AEs and HRQoL were assessed at different time intervals in the two studies, with more frequent assessments in SPARTAN compared with PROSPER. Further, HRQoL changes were only compared at baseline versus end of follow-up. Therefore, it is possible that a selection bias in favor of patients with a good tolerability profile was introduced by the exclusion of patients who discontinued therapy. Finally, follow-up time at which HRQoL was assessed differed slightly between the studies (96 weeks for SPARTAN and 97 weeks for PROSPER).