Health-related quality of life, pain, and symptomatic skeletal events with [¹⁷⁷Lu]Lu-PSMA-617 in patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): an open-label, randomised, phase 3 trial

Background: In the PSMAfore study, lutetium-177 [¹⁷⁷Lu]Lu-PSMA-617 (vipivotide tetraxetan) significantly improved radiographic progression-free survival compared with change of androgen receptor pathway inhibitor (ARPI) in taxane-naive patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer. Here, we present in-depth analyses of time to worsening of health-related quality of life (HRQOL) and pain, and time to first symptomatic skeletal events. Methods: PSMAfore, an open-label, randomised, phase 3 trial, was conducted at 74 investigator sites (including hospitals with nuclear medicine departments and the research facilities where patients were recruited) across 14 countries. Eligible patients had metastatic castration-resistant prostate cancer, were candidates for ARPI change after one progression on a previous ARPI, had at least one PSMA-positive and no exclusionary PSMA-negative metastatic lesions by gallium-68 [⁶⁸Ga]Ga-PSMA-11 PET–CT, were aged 18 years or older, and had an Eastern Cooperative Oncology Group performance status of 0–1. Patients were randomly assigned (1:1) to [¹⁷⁷Lu]Lu-PSMA-617 (7·4 GBq; every 6 weeks for six cycles) or ARPI change (oral abiraterone or enzalutamide per local labelling). The primary endpoint was radiographic progression-free survival. Secondary endpoints included time to worsening in self-reported HRQOL (assessed using the Functional Assessment of Cancer Therapy-Prostate [FACT-P] and EQ-5D-5L) and pain (assessed using the Brief Pain Inventory-Short Form [BPI-SF]) and time to the first symptomatic skeletal event. All analyses were done using the intention-to-treat principle. The study met the primary endpoint of radiographic progression-free survival (reported previously), and overall survival follow-up is ongoing; present analyses are from the third interim analysis of overall survival. This trial is registered with ClinicalTrials.gov, NCT04689828. Findings: Between June 15, 2021, and Oct 7, 2022, 468 patients (426 [91%] were White and 12 [3%] were Black or African American) were randomly assigned to [¹⁷⁷Lu]Lu-PSMA-617 (n=234) or ARPI change (n=234). Median follow-up time from randomisation to the third interim analysis data cutoff date (Feb 27, 2024) was 24·11 months (IQR 20·24–27·60) in the [¹⁷⁷Lu]Lu-PSMA-617 group and 24·13 months (20·24–27·37) in the ARPI change group. [¹⁷⁷Lu]Lu-PSMA-617 delayed time to worsening in all assessed FACT-P, EQ-5D-5L, and BPI-SF scales and subscales versus ARPI change. In the [¹⁷⁷Lu]Lu-PSMA-617 versus ARPI change groups, median time to worsening in FACT-P total score was 7·46 months (95% CI 6·08–8·54) versus 4·27 months (3·45–4·50; hazard ratio [HR] 0·61 [95% CI 0·50–0·75]), in EQ-5D-5L utility score was 6·28 months (4·70–7·89) versus 3·88 months (3·25–4·44; 0·67 [0·54–0·82]), and in BPI-SF pain intensity was 5·03 months (4·40–6·80) versus 3·65 months (3·09–4·37; 0·72 [0·59–0·88]). [¹⁷⁷Lu]Lu-PSMA-617 also delayed symptomatic skeletal events versus ARPI change: median time to first symptomatic skeletal event was not reached (95% CI not estimable [NE]–NE) in the [¹⁷⁷Lu]Lu-PSMA-617 group versus 17·97 months (14·26–NE) in the ARPI change group (HR 0·41 [0·26–0·63]). The most common grade 3 or worse treatment-emergent adverse event was anaemia (14 [6%] of 227 patients in the [¹⁷⁷Lu]Lu-PSMA-617 group vs 16 [7%] of 232 patients in the ARPI change group). There were no treatment-related deaths in the [¹⁷⁷Lu]Lu-PSMA-617 group and one in the ARPI change group (cerebrovascular accident). Interpretation: [¹⁷⁷Lu]Lu-PSMA-617 might delay worsening of patient-reported outcomes and prevent symptomatic skeletal events versus ARPI change in taxane-naive patients with PSMA-positive metastatic castration-resistant prostate cancer whose disease has progressed once on a previous ARPI. Funding: Novartis.