[¹⁷⁷Lu]Lu-PSMA-617 in Metastatic Hormone-Sensitive Prostate Cancer: Evidence from PSMAddition and Considerations for Treatment Sequencing.

Abstract

Introducing [¹⁷⁷Lu]Lu-PSMA-617 into metastatic hormone-sensitive prostate cancer (mHSPC) raises questions about patient selection and treatment sequencing. This non-systematic narrative review examines PSMAddition alongside evidence on alternative treatments, prostate-specific membrane antigen (PSMA) imaging, safety, and subsequent therapy. In the peer-reviewed analysis, with a data cutoff of 13 January 2025, adding radioligand therapy to androgen-deprivation therapy and an investigator-selected androgen receptor pathway inhibitor improved radiographic progression-free survival (hazard ratio 0.72; 95% confidence interval 0.58-0.90). Overall survival was immature and did not meet the prespecified interim significance threshold (hazard ratio 0.84; 95% confidence interval 0.63-1.13). A subsequent non-peer-reviewed sponsor update supported the radiographic findings, although the updated analysis was not controlled for type I error and overall survival remained immature. Radioligand intensification increased grade ≥3 adverse events (51% versus 43%). Prespecified composite quality-of-life and pain endpoints showed no statistically significant differences, although their interpretation is limited by the inclusion of progression or death. Control-arm crossover after progression was optional. Direct mHSPC evidence is distinguished from contextual castration-resistant evidence. Neither a preferred hormonal partner nor superiority over docetaxel-containing triplet therapy has been established. A non-prescriptive five-domain framework integrates target expression, disease characteristics, patient fitness, subsequent treatment options, and delivery capacity to support multidisciplinary assessment.