Determining the Optimal Treatment for Metastatic Castration-resistant Prostate Cancer: Age Should Not Be a Factor

In the current issue of European Urology, Mulder and colleagues report the results of a post hoc subgroup analysis of the COU-AA-301 (postdocetaxel) study focusing on the efficacy and safety of abiraterone in elderly patients (>75 yr of age) [1]. Although overall survival by subgroups was already presented in the final survival analysis of the study [2], these additional data confirm the relative efficacy and safety of abiraterone/prednisone exposure versus placebo/ prednisone in elderly patients. In this trial, 28% of the overall study population was 75 yr or older, allowing analysis of the interaction between age and abiraterone therapy. Treatment with abiraterone acetate yielded improved survival across the two age cohorts. The elderly (>75 yr) subgroup demonstrated hazard ratios (HRs) for death (HR: 0.64; 95% confidence interval [CI], 0.48–0.85) at least equivalent to younger patients (HR: 0.78; 95% CI, 0.65– 0.93). This finding is perhaps unsurprising because multiple trials in this setting have demonstrated similar survival benefits for several active agents in older men with metastatic castration-resistant prostate cancer (mCRPC). For example, post hoc analysis of the AFFIRM trial of enzalutamide demonstrated similar benefit in both older and younger subgroups [3]. Subgroup analysis of the TAX327 study of every 3 wk docetaxel demonstrated similar HRs for overall survival in elderly men using age cutoffs of 69 and 75 yr (HRs: 0.77 and 0.80, respectively, vs 0.81 for younger patients) [4]. A large retrospective study evaluating docetaxel therapy in the elderly in a real-world setting found that elderly patients with a good Eastern Cooperative Oncology Group performance status (PS) responded similarly to younger patients, although unsurprisingly those with a poor PS tolerated docetaxel quite poorly [5]. Because most patients in the COU-AA-301 study had a favorable PS, the relative benefit of this compound in a group of men with advanced age, significant comorbidities, and limited performance status cannot be determined. The extensive experience in mCRPC with various compounds (cytotoxic, radiopharmaceutical, and endocrine drugs) supports that age alone does not reduce the chances of benefit from systemic treatment. Previous concerns have been raised regarding the potential for increased toxicity in the elderly with the potential for polypharmacy/drug interactions and cardiac toxicity given abiraterone’s potential for causing mineralocorticoid excess. The data presented here are largely reassuring on that front, although there was a slightly increased incidence of atrial fibrillation and tachycardia in the elderly treated group, a difference not seen in the younger treated group. Treatment-emergent cardiac events leading to death were seen in only 2% of the elderly treated group versus 1% in the placebo group and 1% in the younger group. Additional follow-up of the COU-AA-302 study will further define the safety of abiraterone as the duration of drug exposure lengthens. An important consideration is that the population of elderly patients presented in this report is highly selected given that they maintained a PS 2, recovered from docetaxel without major functional and medical impairment, and were selected to exclude preexisting cardiac ailments. Extrapolation of the safety of abiraterone to a realworld elderly population should thus be performed with caution. Nevertheless, this study does provide additional evidence that age should not be the major consideration in the choice of therapy and that in elderly men (who were not previously treated with abiraterone, enzalutamide, or