Evaluating the PSMAddition Trial: A Step Forward in mHSPC Treatment

The PSMAddition trial has shown that adding ¹⁷⁷Lu-PSMA-617 to androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI) materially improves radiographic progression-free survival (rPFS) in patients with PSMA‑positive metastatic hormone‑sensitive prostate cancer (mHSPC). The rPFS effect was both statistically and clinically meaningful, signaling deeper early disease control in this molecularly selected population and marking a substantive advance in first‑line disease management.

The randomized phase 3 study enrolled 1,144 patients with PSMA‑positive mHSPC and reached a median follow‑up of 23.6 months. The analysis demonstrated a statistically significant rPFS improvement favoring the arm that received ¹⁷⁷Lu‑PSMA‑617 in addition to ADT plus an ARPI, with consistent directionality across prespecified subgroups.

However, safety data highlight a clear tradeoff: 50.7% of patients in the ¹⁷⁷Lu‑PSMA‑617 arm experienced grade 3 or higher adverse events. Hematologic toxicities — including anemia, neutropenia, and thrombocytopenia — were more frequent with the radioligand, alongside common all‑grade effects such as dry mouth and fatigue. The toxicity profile therefore requires intensified hematologic monitoring, proactive management of symptomatic xerostomia, and careful consideration of baseline marrow reserve when selecting patients.

Key unanswered questions remain: whether the rPFS improvement will translate into an overall survival benefit with longer follow‑up, how benefit distributes across prespecified subgroups, and which operational factors will influence real‑world integration of radioligand therapy into routine mHSPC care.