Dataset Information

Apalutamide Compared with Darolutamide for the Treatment of Non-metastatic Castration-Resistant Prostate Cancer: Efficacy and Tolerability in a Matching-Adjusted Indirect Comparison.

ABSTRACT:

Introduction

Apalutamide and darolutamide are next-generation androgen receptor inhibitors that have demonstrated superior efficacy compared to placebo in men with non-metastatic castration-resistant prostate cancer (nmCRPC) receiving androgen deprivation therapy (ADT). In the absence of head-to-head studies, the present study sought to indirectly compare the efficacy and tolerability between these two treatments.

Methods

This anchored matching-adjusted indirect comparison (MAIC) used patient-level data from the phase 3, randomized, controlled SPARTAN study (apalutamide + ADT), weighted to match aggregate published data from the ARAMIS study (darolutamide + ADT) for clinically relevant baseline measures. Hazard ratios (HR) and 95% credible intervals (CrI) were estimated for efficacy endpoints: metastasis-free survival (MFS), prostate-specific antigen (PSA) progression, progression-free survival (PFS), and overall survival (OS). Odds ratios were estimated for tolerability outcomes: adverse events and serious adverse events.

Results

Before weighting, baseline characteristics from SPARTAN versus ARAMIS were different for median PSA (7.8 vs. 9.2 ng/mL), Eastern Cooperative Oncology Group performance status of 1 (23% vs. 31%), use of bone-targeted agents (10% vs. 4%), median time from initial diagnosis (94.9 vs. 85.4 months), and proportion of patients from North America (35% vs. 12%) and Europe (50% vs. 64%). After matching (n = 455), our analysis demonstrated that apalutamide + ADT had a Bayesian probability of being more effective than darolutamide + ADT for MFS [98.3%; HR 0.70 (95% CrI 0.51, 0.98)], PSA progression [~ 100%; HR 0.46 (95% CrI 0.33, 0.64)], and PFS [93.2%; HR 0.79 (95% CrI 0.59, 1.08)]. Results for OS and tolerability were similar between apalutamide + ADT and darolutamide + ADT.

Conclusion

This anchored MAIC analysis of pivotal phase 3 studies in patients with nmCRPC suggests that apalutamide + ADT is more effective than darolutamide + ADT for MFS, progression-free survival (PFS), and prostate-specific antigen (PSA) progression, with a similar OS benefit and tolerability profile.

Trial registration

ARAMIS ClinicalTrials.gov number: NCT02200614; SPARTAN ClinicalTrials.gov number: NCT01946204.

SUBMITTER: Chowdhury S

PROVIDER: S-EPMC8799579 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTo date, the efficacy of the androgen receptor inhibitors enzalutamide and apalutamide for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) has not been compared directly in a clinical trial setting. Indirect comparisons can be used to assess relative efficacy and provide important information to guide treatment decisions. PROSPER and SPARTAN were double-blind, randomized, placebo-controlled, phase III trials in patients with nmCRPC with overall similar study designs and inclusion and exclusion criteria. Using an anchored matching-adjusted indirect comparison, based on the final data from the PROSPER and SPARTAN studies, we assessed the comparative efficacy of enzalutamide and apalutamide, both plus androgen deprivation therapy.MethodsUsing placebo as the common comparator, individual patient data from PROSPER were matched to the aggregate patient data from SPARTAN and efficacy endpoints from PROSPER were re-weighted accordingly. Patient baseline characteristics and endpoints were clinically and statistically tested to identify potential effect modifiers, according to National Institute for Health and Care Excellence guidelines. Hazard ratios for overall survival (OS), metastasis-free survival (MFS), and time to chemotherapy (TTCx) were re-estimated for PROSPER using weighted Cox proportional hazards models and indirectly compared with those of SPARTAN using a Bayesian network meta-analysis.ResultsEstimated hazard ratios [95% credible interval (CrI)] for enzalutamide versus apalutamide were 0.80 (95% CrI 0.58-1.10) for OS, 0.94 (95% CrI 0.69-1.29) for MFS2, and 0.90 (95% CrI 0.63-1.29) for TTCx. Similar results were seen for sensitivity analyses conducted for OS and MFS. Bayesian probability analyses showed a 91.7% favoring enzalutamide for OS, 65.1% for MFS, and 71.4% for TTCx.ConclusionsThe results of this matching-adjusted indirect comparison of final data from PROSPER and SPARTAN indicate comparable efficacy of enzalutamide and apalutamide with potentially a greater probability of longer MFS, OS, and TTCx in patients with nmCRPC treated with enzalutamide versus apalutamide.

Project description:BackgroundFor nonmetastatic castration-resistant prostate cancer (nmCRPC), 3 drugs under patent protection-apalutamide, enzalutamide, and darolutamide-were approved based on randomized, placebo-controlled trials; 1 drug with generic availability, abiraterone acetate, showed efficacy in a single-arm trial and is commonly prescribed. Lacking head-to-head trials, the optimal treatment for nmCRPC is unknown, despite widely varied treatment costs. We compared the efficacy and safety of nmCRPC treatments.MethodsWe searched bibliographic databases, regulatory documents, and trial registries for nmCRPC trials. We included published results and, when available, original data. We performed matching-adjusted indirect comparison and network meta-analysis and compared treatments regarding metastasis-free survival, overall survival, and serious adverse events.ResultsWe analyzed 5 trials with 4360 participants. Compared with placebo, abiraterone acetate engendered the lowest hazard of metastasis and death (hazard ratio [HR] = 0.22, 95% credible interval [CrI] = 0.12-0.41), followed by apalutamide (HR = 0.28, 95% CrI = 0.23-0.34), enzalutamide (HR = 0.30, 95% CrI = 0.25-0.36), and darolutamide (HR = 0.41, 95% CrI = 0.34-0.49); darolutamide led to the lowest hazard of death (HR = 0.69, 95% CrI = 0.53-0.90), followed by enzalutamide (HR = 0.73, 95% CrI = 0.61-0.87) and apalutamide (HR = 0.75, 95% CrI = 0.59-0.95); darolutamide resulted in the lowest odds of serious adverse events (odds ratio [OR] = 1.32, 95% CrI = 1.02-1.70), followed by enzalutamide (OR =1.43, 95% CrI = 1.08-1.89), apalutamide (OR = 1.58, 95% CrI = 1.23-2.03), and abiraterone acetate (OR = 1.94, 95% CrI = 1.17-3.22).ConclusionsFor nmCRPC, darolutamide offered optimal efficacy and safety among approved drugs, and abiraterone acetate may offer comparable metastasis-free survival benefit with cost savings from generic availability. Future research is needed to more fully examine the benefit of abiraterone acetate.

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