Doublet Versus Triplet Therapy in High-volume Metastatic Hormone-sensitive Prostate Cancer Patients with Bone Metastases: Results from the ARON-3 Study

Background and objective: Data for direct comparison of the outcomes for androgen-deprivation therapy (ADT) + androgen signaling pathway-inhibitors (ARPI) versus ADT + ARPI + docetaxel are scant, especially in patients with high-volume metastatic hormone-sensitive prostate cancer (mHSPC), according to CHAARTED classification and regarding to the number of bone metastases. Design, setting and paticipants: Relying on the multicentric international ARON-3 database, patients with high-volume mHSPC with bone metastases undergoing doublet versus triplet therapy were selected and stratified according to the number of bone metastases (≤10 vs >10). Primary endpoints consisted of time to treatment failure (TTF), prostate-specific antigen-response, and overall survival (OS). Results and limitations: Overall, 841 patients treated with doublet (75%) or triplet (25%) therapy were included. At 12 wk, triplet therapy was associated with changes in opioid use and in Eastern Cooperative Oncology Group performance status. Median OS was 63.0 mo for ADT + abiraterone acetate and was not reached for ADT + apalutamide, ADT + enzalutamide, and ADT + docetaxel + darolutamide. Differences in adjusted TTF estimates between treatment groups were observed in patients with >10 bone metastases (hazard ratio [HR] 0.49, 95% confidence interval [CI] 0.28-0.87; p = 0.02), whereas adjusted OS estimates also differed numerically but were not statistically significant (HR 0.48, 95% CI 0.21-1.07; p = 0.1). In patients with concomitant visceral metastases, TTF and OS estimates also differed numerically by treatment group; however, these differences were not statistically significant. Conclusions: In exploratory subgroup analyses, TTF and OS estimates varied by bone metastatic burden, but formal interaction testing did not show evidence of heterogeneity. These findings require prospective validation.