[ 177 Lu]Lu-PSMA-617 in patients with PSMA-positive metastatic androgen pathway modulator-naive/sensitive prostate cancer (PSMAddition): a phase 3 randomised, controlled trial.

A contemporary standard of care for patients with metastatic androgen pathway modulator-naive/sensitive (APMN/S) prostate cancer (also known as metastatic hormone-sensitive prostate cancer) is androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI) until progression. PSMAddition aimed to evaluate the efficacy and safety of [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) combined with ADT plus ARPI in prostate-specific membrane antigen (PSMA)-positive metastatic APMN/S prostate cancer. PSMAddition is an ongoing, randomised, controlled, phase 3 superiority trial conducted at 169 sites across 20 countries, including hospitals, medical centres, and specialist cancer centres. Eligible male patients had treatment-naive or minimally treated metastatic APMN/S prostate cancer diagnosed by CT, MRI, or bone scan and one or more PSMA-positive metastatic lesion on centrally read baseline [ 68 Ga]Ga-PSMA-11 PET. Patients were randomly assigned 1:1 to open-label, intravenous 177 Lu-PSMA-617 (7·4 GBq [200 mCi] ±10% every 6 weeks for up to six cycles) with ADT plus ARPI ( 177 Lu-PSMA-617 arm) or ADT plus ARPI (control arm). ADT and ARPI were investigator-chosen according to local authorisation and administered per local product labelling. Control arm patients with centrally confirmed radiographic progression could cross over to 177 Lu-PSMA-617. The primary endpoint was radiographic progression-free survival (centrally assessed per Prostate Cancer Clinical Trials Working Group 3-modified RECIST 1.1 or death); secondary endpoints included safety and tolerability. We report the second interim analysis of radiographic progression-free survival in the intention-to-treat population (all randomly assigned participants; data cutoff Jan 13, 2025). Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04720157, and is ongoing. From June 15, 2021, to July 25, 2023, 1529 patients were screened and 1144 were randomly assigned (n=572 per arm; 1144 [100%] male, 572 [50%] with de novo metastatic APMN/S prostate cancer, 779 [68%] with high-volume disease; median age 68·0 years [IQR 62·0-73·0]). Baseline characteristics were balanced between arms. At second interim analysis for radiographic progression-free survival (median time from randomisation to data cutoff 23·6 months [IQR 20·3-29·2]; median radiographic progression-free survival follow-up time 19·6 months [IQR 14·0-24·1]), 139 (24%) of 572 participants in the 177 Lu-PSMA-617 arm and 172 (30%) of 572 participants in the control arm had radiographic disease progression or death. Radiographic progression-free survival was significantly improved in the 177 Lu-PSMA-617 arm versus the control arm, with a 28% reduction in the relative risk of radiographic progression or death (HR 0·72 [95% CI 0·58-0·90]; p=0·0021; median radiographic progression-free survival not reached in either arm). The primary endpoint was thus met. Grade 3 or worse adverse events occurred in 286 (51%) of 564 patients in the 177 Lu-PSMA-617 arm and 243 (43%) of 565 patients in the control arm. Serious adverse events occurred in 180 (32%) of 564 patients in the 177 Lu-PSMA-617 arm and 162 (29%) of 565 in the control arm; of which 17 (3%) in the 177 Lu-PSMA-617 arm were 177 Lu-PSMA-617-related. The most common adverse event was dry mouth, in 258 (46%) patients in the 177 Lu-PSMA-617 arm and 21 (4%) patients in the control arm; all were grade 1 or 2 and none were serious. Other common adverse events with higher incidence in the 177 Lu-PSMA-617 arm included cytopenias and gastrointestinal disturbances. Combining 177 Lu-PSMA-617 with ADT plus ARPI prolonged radiographic progression-free survival in patients with PSMA-positive metastatic APMN/S prostate cancer. Although adverse events were more frequent, there were no unexpected safety findings associated with the drug combination. Therefore, combining 177 Lu-PSMA-617 with ADT plus ARPI might be a new treatment option in metastatic APMN/S prostate cancer. Novartis.