In a U.S. Food and Drug Administration pooled analysis of clinical trial patient-level data reported in The Lancet Oncology, Fallah et al found that second-generation androgen receptor inhibitor treatment was associated with survival benefits in patients aged 80 years or older with nonmetastatic castration-resistant prostate cancer. However, older patients were at increased risk of adverse events vs younger patients irrespective of receipt of androgen receptor inhibitors or placebo.
Study Details
The study involved data from three randomized trials identified through August 2020 evaluating the use of apalutamide, enzalutamide, or darolutamide vs placebo; patients in all trials had a prostate-specific antigen (PSA) level of ≥ 2.0 μg/L, a PSA doubling time of ≤ 10 months, and no evidence of distant metastatic disease. The effect of age (younger than 80 or aged 80 or older) on metastasis-free and overall survival was assessed in the intention-to-treat population. Analyses were adjusted for baseline performance status, Gleason score, PSA doubling time, use of bone-targeting agents, and receipt of previous prostatectomy or radiotherapy.
The findings of this pooled analysis support the use of androgen receptor inhibitors in older men with nonmetastatic castration-resistant prostate cancer. Incorporating geriatric assessment tools in the care of older adults with nonmetastatic castration-resistant prostate cancer might help clinicians to offer individualized treatment to each patient.— Fallah et al
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Key Findings
In the three trials, 4,117 patients were assigned between October 2013 and March 2018 to receive treatment with an androgen receptor inhibitor (apalutamide, enzalutamide, or darolutamide; n = 2,694) or placebo (n = 1,423). Median follow-up was 18 months (interquartile range [IQR] = 11–26 months) for metastasis-free survival and 44 months (IQR = 32–55 months) for overall survival.
Among 1,023 patients aged 80 or older, the estimated median metastasis-free survival was 40 months (95% confidence interval [CI] = 36–41 months) in the androgen receptor–inhibitor group (n = 675) vs 22 months (95% CI = 18–29 months) in the placebo group (n = 348), with an adjusted hazard ratio of 0.37 (95% CI = 0.28–0.47). Median overall survival was 54 months (95% CI = 50–61 months) vs 49 months (95% CI = 43–58 months), with an adjusted hazard ratio of 0.79 (95% CI = 0.64–0.98).
Among 3,094 patients younger than age 80, estimated median metastasis-free survival was 41 months (95% CI = 36 months to not estimable) in the androgen receptor–inhibitor group (n = 2,019) vs 16 months (95% CI = 15–18 months) in the placebo group (n = 1,075), with an adjusted hazard ratio of 0.31 (95% CI = 0.27–0.35). Median overall survival was 74 months (95% CI = 74 months to not estimable) vs 61 months (95% CI = 56 months to not estimable), with an adjusted hazard ratio of 0.69 (95% CI = 0.60–0.80).
Grade ≥ 3 adverse events were reported in 55% of the androgen receptor–inhibitor group vs 41% of the placebo group among patients aged ≥ 80 years and in 44% of the androgen receptor–inhibitor group vs 30% of the placebo group among those aged < 80 years. The most common grade 3 or 4 adverse events were hypertension (8% and 8% of patients aged < 80 and ≥ 80 years in the androgen receptor–inhibitor groups vs 5% and 6% in the placebo groups) and fracture (3% and 5% in the androgen receptor–inhibitor groups vs 1% and 3% in the placebo groups).
The investigators concluded: “The findings of this pooled analysis support the use of androgen receptor inhibitors in older men with nonmetastatic castration-resistant prostate cancer. Incorporating geriatric assessment tools in the care of older adults with nonmetastatic castration-resistant prostate cancer might help clinicians to offer individualized treatment to each patient.”
Jaleh Fallah, MD, of the Center for Drug Evaluation and Research, Office of Oncologic Diseases, U.S Food and Drug Administration, is the corresponding author of The Lancet Oncology article.
Disclosure: There was no external funding for the study. For full disclosures of the study authors, visit thelancet.com.
