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
- PMID: 40441170
- DOI: 10.1016/S1470-2045(25)00189-5
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
Abstract
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.
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Conflict of interest statement
Declaration of interests KF reports receiving institutional honoraria or payments to Gustave Roussy Institute from Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis, and Sanofi; institutional participation on data safety monitoring or advisory boards for Amgen, Astellas, AstraZeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis, Pfizer, and Sanofi; and personal participation on a data safety monitoring or advisory board for Arvinas, CureVac, Macrogenics, and Orion. MJM reports receiving consulting or advisory fees from Amgen, AstraZeneca, Blue Earth Diagnostics, Clarity Pharmaceuticals, Convergent Therapeutics, Daiichi, ITM Isotope Technologies Munich, Lantheus Medical Imaging, Pfizer, POINT Biopharma, Progenics, Telix Pharmaceuticals, and Z-Alpha; stock and other ownership in Doximity; travel, accommodations, and expenses from APCCC, AstraZeneca, and Memorial Sloan-Kettering Cancer Center (MSKCC; the work at MSKCC was supported by the US National Cancer Institute Core Grant #P30 CA008748); institutional research funding from Astellas Pharma, Bayer, Celgene, Corcept Therapeutics, Janssen, Novartis, Progenics, and Roche/Genentech; and royalties from Telix. NDS reports research and consulting fees from Allessa, Amgen, Artera, Astellas, AstraZeneca, Aura Biosciences, Bayer, BMS, Caris, CG Oncology, Daiichi Sankyo, Dendreon, Glytheryx, Invitae, Janssen, MDxhealth, Merck, Minomic, Novartis, Nusano, Photocure, Pfizer, Sumitomo, Telix, Tolmar, Tutelix, and Urogen. KNC reports receiving grants or contracts from AstraZeneca, Bayer, Janssen, Merck, Novartis, Pfizer, POINT Biopharma, and Roche; and consulting fees from Astellas, AstraZeneca, Bayer, Janssen, Merck, Novartis, Pfizer, POINT Biopharma, and Roche. MC reports consulting fees from Astellas, AstraZeneca, Blue Earth Diagnostics, Boston Scientific, Elekta, Johnson & Johnson, Lantheus, Macrogenics, Pfizer, Profound Medical, Sumitomo, Telix, Tolmar, and Tempus; payments or honoraria from Johnson & Johnson, Pfizer, Profound Medical, and Telix; participating on an advisory board for Telix; and having a leadership or fiduciary role for the Society of Nuclear Medical and Molecular Imaging and the American Urological Association. JSdB has served on advisory boards and received fees from many companies including AbbVie, Acai Therapeutics, Amgen, Amunix, Astellas, Bayer, Bioxcel Therapeutics, Celcuity, Crescendo, Daiichi, Dark Blue Therapeutics, Duke Street Bio, Dunad Therapeutics, Endeavor BioMedicines, Genentech/Roche, GSK, Macrogenics, Merck Serono, MetaCurUm, Moma, Myricx, Novartis, Nurix Therapeutics, Nuvation Bio, One-Carbon Therapeutics, Oncternal, Orion, Page Therapeutics, Peptone, Pfizer, Takeda, Tango Therapeutics, Tubulis, and VIR Biotechnology; is an employee of the Institute of Cancer Research, which has received funding or other support for his research work from AstraZeneca, Cellcentric, Crescendo, Daiichi, Eikon Therapeutics, Immunic Therapeutics, MetaCurUm, Myricx, Nurix Therapeutics, Oncternal, Orion, Sanofi Aventis and which has a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers, and PI3K–AKT pathway inhibitors (no personal income); is named as an inventor, with no financial interest for patent 8,822,438, submitted by Janssen that covers the use of abiraterone acetate with corticosteroids; has been the chief or principal investigator of many industry-sponsored clinical trials; and is a UK National Institute for Health and Care Research (NIHR) Senior Investigator (the views expressed in this article are those of the author[s] and not necessarily those of the UK National Health Service, NIHR, or Department of Health). KH reports receiving grants or contracts from Boston Scientific, Janssen, and Novartis; consulting fees from Amgen, AstraZeneca, Bain Capital, Bayer, Boston Scientific, Convergent, Curium, Debiopharm, EcoR1, Fusion, GE Healthcare, Immedica, ITM Isotope Technologies Munich, Janssen, Merck, Molecular Partners, Novartis, NVision, POINT Biopharma, Pfizer, Radiopharm Theranostics, Rhine Pharma, Siemens Healthineers, Sofie Biosciences, Telix, Theragnostics, and YmAbs Therapeutics; and stock or other ownership in AdvanCell, Aktis Oncology, Convergent, NVision, Pharma 15, and Sofie Biosciences. GR reports receiving grants or contracts from Bayer, and consulting fees from Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis, and Pfizer. MF reports receiving speaker fees from Novartis. NC, SG, and MH report being employed by and receiving restricted stock options from Novartis. DC reports receiving payments or honoraria from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis, Eisai, Exelisis, GlaxoSmithKline, Ipsen, Janssen, Lilly, MSD, Pfizer, QED Therapeutics, and Roche; travel or other expenses from Astellas, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; participation on a data safety monitoring or advisory board for Astellas, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; and other financial or non-financial interests in Spanish Oncology Genito-Urinary Group Foundation, and GUARD Consortium Spanish group. OS reports institutional grants or contracts from Amgen, AstraZeneca, Bayer, Endocyte, Invitae, Janssen, Lantheus, Merck, Modex Therapeutics, Norroy Bioscience, Novartis, Preceded Biosciences, Progenics, and Tenebio; consulting fees from ARTBIO, AstraZeneca, Bayer, Blue Earth Diagnostics, Clarity Pharmaceuticals, Fusion, ITM Isotope Technologies Munich, Janssen, Merck, Myovant, Myriad, Noria Therapeutics, NorthStar, Novartis, Pfizer, POINT Biopharma, Sanofi, Telix, and Tenebio; travel and accommodation expenses from Lantheus, NorthStar, and Novartis; participation on a data safety monitoring or advisory board for AstraZeneca, Merck, and Pfizer; and stock or stock options in ARTBIO, Clarity Pharmaceuticals, Convergent, Fusion, Lilly, Pfizer, Ratio, and Telix. All other authors declare no competing interests.
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