Androgen Receptor Inhibitors in Patients With Nonmetastatic Castration-Resistant Prostate Cancer

Abstract

Importance: Novel androgen receptor inhibitors (ARIs; darolutamide, enzalutamide, and apalutamide) are standard-of-care treatments for nonmetastatic castration-resistant prostate cancer (nmCRPC). However, there are sparse data comparing their clinical use and tolerability.

Objective: To compare clinical use and outcomes for darolutamide, enzalutamide, and apalutamide in patients with nmCRPC.

Design, setting, and participants: This retrospective cohort study reviewed electronic medical records from the Precision Point Specialty network of US urology practices. Eligible patients had nmCRPC and no prior novel hormonal therapy and initiated novel ARI treatment between August 1, 2019, and March 31, 2022. Data were analyzed from February 1, 2019, to December 31, 2022.

Exposures: Patients were prescribed darolutamide, enzalutamide, or apalutamide as their first novel ARI for nmCRPC.

Main outcomes and measures: The main outcome was a composite of 2 end points, treatment discontinuation and progression to metastatic CRPC (mCRPC), whichever occurred first. Both end points were also assessed separately.

Results: All 870 patients meeting eligibility criteria were included (362 receiving darolutamide [41.6%]; 382, enzalutamide [43.9%]; 126, apalutamide [14.5%]); mean (SD) age was 78.8 (8.7) years. Self-reported race was Black or African American in 187 patients (21.5%), White in 585 (67.2%), and other or unknown in 98 (11.3%). The darolutamide cohort had lower proportions of patients with a composite end point event (134 [37.0%] vs 201 [52.6%] for enzalutamide and 66 [52.4%] for apalutamide), discontinuation (110 [30.4%] for darolutamide vs 156 [40.8%] for enzalutamide and 58 [46.0%] for apalutamide), and progression to mCRPC (64 [17.7%] for darolutamide vs 108 [28.3%] for enzalutamide and 35 [27.8%] for apalutamide) during the study period. After adjusting for baseline covariates, patients receiving darolutamide had a lower risk of a composite end point event compared with enzalutamide (risk reduction, 33.8%; hazard ratio [HR], 0.66 [95% CI, 0.53-0.84]) and apalutamide (risk reduction, 35.1%; HR, 0.65 [95% CI, 0.48-0.88]). Similarly, patients receiving darolutamide had a lower risk of discontinuation compared with enzalutamide (risk reduction, 27.4%; HR, 0.73 [95% CI, 0.56-0.94]) and apalutamide (risk reduction, 39.1%; HR, 0.61 [95% CI, 0.44-0.85]) and a lower risk of progression to mCRPC compared with enzalutamide (risk reduction, 40.6%; HR, 0.59 [95% CI, 0.43-0.82]) and apalutamide (risk reduction, 35.3%; HR, 0.65 [95% CI, 0.42-0.99]). There was no difference between enzalutamide and apalutamide treatment across outcomes.

Conclusions and relevance: In this large cohort study of patients with nmCRPC treated with novel ARIs, results suggest better tolerability for darolutamide compared with enzalutamide and apalutamide, which may be associated with a clinical effectiveness advantage. Comparative clinical studies are needed to guide treatment decisions in the absence of head-to-head clinical trials.

Figure 1.. Composite End Point of Time to Initial Androgen Receptor Inhibitor (ARI) Therapy Discontinuation or Progression to Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Composite end point was defined as the earliest occurrence of evidence of stopping initial ARI treatment, switch to another ARI, evidence of metastatic lesion(s), diagnosis of mCRPC, drug treatment initiated specifically for mCRPC (ie, abiraterone acetate, docetaxel, cabazitaxel, sipuleucel-T, mitoxantrone hydrochloride, or radium RA 223 dichloride), or death. The dashed line indicates posterior probability of 0.5. A total of 791 patients (328 receiving darolutamide, 341 receiving enzalutamide, and 122 receiving apalutamide) were included in the Cox proportional hazards regression model after excluding 79 patients with unknown insurance coverage and/or missing baseline prostate-specific antigen (PSA) values. The following observed baseline characteristics were included in the adjusted Cox proportional hazards regression models: age group at index (≤74, 75-84, or ≥85 years), race (Black or African American, White, or other or unknown), insurance coverage (commercial or public), index period (2019-2020 or 2021-2022), baseline PSA group (<2, 2 to <10, or ≥10 ng/mL), baseline PSA doubling time group (≤6, >6 to ≤10, or >10 months or missing), time from non-mCRPC diagnosis to index date (months), and Gleason score at initial prostate cancer diagnosis (4-7, 8-10, or missing). HR indicates hazard ratio. ^aNumbers of patients at risk were calculated at the start of each time point.

Figure 2.. Time to Initial Androgen Receptor Inhibitor (ARI) Therapy Discontinuation

Discontinuation of initial ARI treatment was defined as the earliest occurrence of stopping initial ARI treatment, switch to another ARI, or death. The dashed line indicates posterior probability of 0.5. A total of 791 patients (328 receiving darolutamide, 341 receiving enzalutamide, and 122 receiving apalutamide) were included in the Cox proportional hazards regression model after excluding 79 patients with unknown insurance coverage and/or missing baseline prostate-specific antigen (PSA) values. The following observed baseline characteristics were included in the adjusted Cox proportional hazards regression models: age group at index (≤74, 75-84, or ≥85 years), race (Black or African American, White, or other or unknown), insurance coverage (commercial or public), index period (2019-2020 or 2021-2022), baseline PSA group (<2, 2 to <10, or ≥10 ng/mL), baseline PSA doubling time group (≤6, >6 to ≤10, or >10 months or missing), time from non-mCRPC diagnosis to index date (months), and Gleason score at initial prostate cancer diagnosis (4-7, 8-10, or missing). ^aNumbers of patients at risk were calculated at the start of each time point.

Figure 3.. Reasons for Initial Androgen Receptor Inhibitor (ARI) Therapy Discontinuation as Assessed by the Treating Physician

All percentages are rounded to the nearest integer. Other includes additional miscellaneous reasons, such as cost, physician decision, patient decision or withdrawal, rise in prostate-specific antigen level, and moved to oncology practice. AE indicates adverse event; mCRPC, metastatic castration-resistant prostate cancer.

Figure 4.. Time to Progression to Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Progression to mCRPC was defined as the earliest occurrence of a clear diagnosis of mCRPC, evidence of metastasis in patient medical records or radiology reports, or drug treatment initiated specifically for mCRPC (ie, abiraterone acetate, docetaxel, cabazitaxel, sipuleucel-T, mitoxantrone hydrochloride, or radium RA 223 dichloride). The dashed line indicates posterior probability of 0.5. A total of 791 patients (328 receiving darolutamide, 341 receiving enzalutamide, and 122 receiving apalutamide) were included in the Cox proportional hazards regression model after excluding 79 patients with unknown insurance coverage and/or missing baseline prostate-specific antigen (PSA) values. The following observed baseline characteristics were included in the adjusted Cox proportional hazards regression models: age group at index (≤74, 75-84, or ≥85 years), race (Black or African American, White, or other or unknown), insurance coverage (commercial or public), index period (2019-2020 or 2021-2022), baseline PSA group (<2, 2 to <10, or ≥10 ng/mL), baseline PSA doubling time group (≤6, >6 to ≤10, or >10 months or missing), time from non-mCRPC diagnosis to index date (months), and Gleason score at initial prostate cancer diagnosis (4-7, 8-10, or missing). ^aNumbers of patients at risk were calculated at the start of each time point.