Study supports use of androgen receptor inhibitors in older men with nmCRPC

The results of a recent FDA database analysis support the use of the androgen receptor inhibitors (ARIs) apalutamide (Erleada), enzalutamide (Xtandi), and darolutamide (Nubeqa) in men aged ≥80 years with nonmetastatic castration-resistant prostate cancer (nmCRPC).1

For the analysis, researchers from the FDA’s Center for Drug Evaluation and Research pooled data from 3 clinical trials (SPARTAN [NCT01946204], PROSPER [NCT02003924], and ARAMIS [NCT02200614]) in which ARIs were compared with placebo in patients with nmCRPC. The researchers noted that although toxicity was increased with ARIs versus placebo, the overall benefit-risk analysis supported use of ARIs in older patients.

“The results of this exploratory analysis are important in clinical decision making, particularly for men aged older than 80 years, for whom there is little information in each product label regarding the risks and benefits of treatment with androgen receptor inhibitors for non-metastatic castration-resistant prostate cancer. Shared decision-making regarding efficacy, toxicity, and quality of life measures could be informed by these data,” the investigators wrote.

The pooled analysis included 4117 patients with nmCRPC randomized across the 3 trials to an ARI (apalutamide, enzalutamide, or darolutamide; n = 2694) or placebo (n = 1423) between October 14, 2013, and March 9, 2018. The data were obtained from the FDA’s Document Archiving, Reporting, and Regulatory Tracking System. The median age at baseline was 74 years (range, 48-97). All patients had an ECOG performance status of 0to 1, a baseline PSA level ≥2 μg/L, a PSA doubling time of ≤10 months, and no evidence of distant metastases at screening.

“There was no marked difference in any of the baseline characteristics between the treatment groups within each age group,” the investigators wrote. Of note, 60% of patients (612 of 1023) aged ≥80 years had not received prostatectomy or radiotherapy prior to enrollment, compared with 41% (1254 of 3094) of patients aged <80 years. More patients aged ≥80 years had an ECOG performance status of 1 versus patients aged <80 years; however, the <80 years cohort had higher Gleason scores and shorter PSA doubling times at diagnosis compared with the older cohort.

The median follow-up times were 18 months (interquartile range [IQR], 11-26) for metastasis-free survival (MFS) and 44 months (IQR, 32-55) for overall survival (OS). Among patients aged ≥80 years, the median MFS was 40 months with ARIs versus 22 months with placebo (HR, 0.37) and the median OS was 54 versus 49 months, respectively (HR, 0.79). In the cohort of patients aged <80 years, the estimated MFS was 41 months with ARIs versus 16 months with placebo (HR, 0.31). The median OS was 74 months versus 61 months, respectively (HR, 0.69).

The safety analysis included 4104 patients who received at least 1 dose of study treatment. Among the patients aged ≥80 years, 55% (371 of 672) of patients receiving ARIsexperienced grade ≥3 adverse events (AEs) compared with 41% (140 of 344) of patients receiving placebo. In the cohort of patients aged <80 years, the rates were 44% (878 of 2015) versus 30% (321 of 1073), respectively.

The 2 most common grade 3/4 AEs were hypertension and ­fracture. Among patients aged <80 years, 8% of patients in the ARI group experienced grade 3/4 hypertension versus 5% of patients receiving placebo. The rates were 8% versus 6%, respectively, in patients aged ≥80 years. Grade 3/4 fracture occurred in 3% of patients aged <80 years receiving ARIs versus 1% in those receiving placebo. The rates were 5% versus 3%, respectively, among patients aged ≥80 years.

In their conclusion, the authors offered advice on how to best use their findings in the clinic going forward. “Incorporating geriatric assessment tools in the care of older adults with prostate cancer might help clinicians to offer individualized treatment to each patient, on the basis of the patient’s health status, and the drug’s safety and efficacy profile.”


1. Fallah J, Zhang L, Amatya A, et al. Survival outcomes in older men with non-metastatic castration-resistant prostate cancer treated with androgen receptor inhibitors: a US Food and Drug Administration pooled analysis of patient-level data from three randomised trials [published online ahead of print July 23, 2021]. Lancet Oncol.doi: 10.1016/ S1470-2045(21)00334-X