Survival Outcomes with Darolutamide, Enzalutamide and Apalutamide in High-Risk Non-Metastatic Castration-Resistant Prostate Cancer
Introduction
Three prospective randomized trials - SPARTAN, PROSPER, and ARAMIS have demonstrated better overall survival (OS) outcomes with apalutamide, enzalutamide and darolutamide as compared to androgen deprivation therapy (ADT) in high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). However, the median follow-up period for each of these androgen receptor-axis-targeted therapies (ARAT) varied as compared to those in the recent studies. The most recent and mature data have not compared the OS and adverse events (AEs) associated with the use of the 3 ARATs. This network meta-analysis (NMA) was conducted to address these gaps.
Aim
This NMA assessed the OS and AEs following treatment with the 3 ARATs and also provided subgroup analyses based on prostate-specific antigen (PSA) doubling time (PSA-DT).
Method
Study Design
- Systematic review and NMA was conducted on most recent studies that focused on OS and AEs with the use of apalutamide, enzalutamide, and darolutamide
- Preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were used to identify the studies that compared the efficacy and toxicity associated with apalutamide vs. enzalutamide vs. darolutamide relative to ADT.
- PubMed database was searched to identify the most recent reports with proven predefined OS benefit, relative to ADT
- This NMA included 3 randomized trials: SPARTAN, PROSPER, and ARAMIS.
Endpoints
- OS defined as the median time from initiation of ADT or combination therapy until the patient’s death
- AEs
Results
- The combined study population from the 3 trials comprised 4117 patients
- The cohort from all the 3 trials had similar median age (73 to 74 years), median baseline PSA (7.8 to 11.1 ng/ml) and median PSA-DT (3.6 to 4.7 months).
- The 3 ARATs had longer OS outcomes as compared to ADT
- The maximal OS benefit was demonstrated with darolutamide, followed by enzalutamide and apalutamide, in that order.
- In the subgroup of patients with PSA-DT ≤ 6 months, enzalutamide was associated with the highest likelihood of providing maximal OS benefit, followed by darolutamide and apalutamide in that order.
- Darolutamide ranked first in providing maximal OS benefit in the subgroup of PSA-DT 6–10 months patients, followed by apalutamide and enzalutamide, in that order.
- Darolutamide had the lowest likelihood of grade 3+ AEs, followed by enzalutamide and apalutamide, in that order.
Conclusion
- The current network meta-analysis (NMA) offers most mature and robust comparisons with respect to overall survival (OS) outcomes of treatment with darolutamide, enzalutamide and apalutamide in high-risk non-metastatic castration-resistant prostate cancer.
- Darolutamide demonstrated highest efficacy and safety as compared to the other 2 drugs.
- However, enzalutamide had the highest efficacy in patients with PSA-DT ≤ 6 months.
- Heterogeneity with respect to study design, maturity, cohort characteristics and follow-up duration should be considered in the interpretation of the current NMA.
Prostate Cancer Prostatic Dis. 2021. Doi:10.1038/s41391-021-00395-4.
