LuPSMA: Another Treatment Option for Metastatic Castration-Resistant Prostate Cancer

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The use of lutetium-177–labeled PSMA-617 (LuPSMA) improved radiographic progression–free survival by 57% in men with metastatic castration-resistant prostate cancer who experienced disease progression on an androgen receptor (AR) pathway inhibitor compared with changing to a new AR pathway inhibitor. These findings from an updated analysis of the phase III PSMAfore trial were reported at a Presidential Symposium during the European Society for Medical Oncology (ESMO) Congress 2023.1 All men in the trial had PSMA-positive metastatic castration-resistant prostate cancer at enrollment.

Median radiographic progression-free survival (the primary endpoint of the trial) was 12 months with LuPSMA vs 5.6 months with a change to a new AR pathway inhibitor. In addition, men taking LuPSMA reported improved quality of life, as well as greater decline in prostate-specific antigen (PSA) levels, longer time to skeletal-related events, and improved health-related quality of life. Data for overall survival are immature, but at the time of this updated analysis, no survival benefit was evident.

“The radiographic progression–free survival data are unequivocally positive. The totality of evidence clearly favors LuPSMA,” said co-principal investigator of the trial, Oliver Sartor, MD, of the Mayo Clinic, Rochester, Minnesota (formerly of Tulane University). “We look forward to a future where LuPSMA may be a viable therapy for patients in need of alternative, earlier options.”

Oliver Sartor, MD

Oliver Sartor, MD

“LuPSMA is an intravenous radioligand therapy for PSMA-positive castration-resistant prostate cancer. It is a beta emitter and can destroy cells where deposited. It is a ligand that binds to PSMA on the surface of tumor cells; after the binding and internalization take place, DNA damage will occur,” Dr. Sartor explained.

LuPSMA is currently approved to treat metastatic castration-resistant prostate cancer in patients previously treated with an AR pathway inhibitor and a taxane. This study explored the use of LuPSMA in those with PSMA-positive disease who had not previously received a taxane.

PSMAfore Details

PSMAfore was a phase III, open-label, multicenter, 1:1 randomized study of 469 patients comparing the efficacy and safety of LuPSMA with a change in AR pathway inhibitor (abiraterone or enzalutamide). Patients had experienced disease progression on a second-generation AR pathway inhibitor (abiraterone, enzalutamide, darolutamide, or apalutamide) and were not candidates for PARP inhibition.

The primary endpoint was radiographic progression–free survival (ie, time from randomization to radiographic disease progression). Dr. Sartor explained that a prespecified crossover overall survival analysis was performed to adjust for the 84% rate of crossover from the AR pathway inhibitor arm.

“We have never seen such a high rate of crossover in a phase III prostate cancer trial,” Dr. Sartor told the audience.

In addition to the statistically significant and clinically meaningful improvement in radiographic progression–free survival, a 50% or greater decline in PSA levels was observed in 57.6% of those assigned to LuPSMA vs 20.4% of those not given LuPSMA. In patients with measurable disease, the complete response rate was 21.1% vs 2.7%.

The risk of symptomatic skeletal events was reduced by 65% in the LuPSMA-treated arm compared with the control arm. Objective radiographic response rate was 50.7% vs 14.9%, respectively. Duration of response was 13.6 months vs 10.1 months, respectively.

The risk of health-related quality-of-life deterioration was 41% improved with -LuPSMA compared with a new AR pathway inhibitor, according to the Functional Assessment of Cancer Therapy–Prostate score, and risk of deterioration was improved by 31%, according to the Brief Pain Inventory–Short Form.

However, survival was not improved at the second interim overall survival analysis. Median survival was about 19 months in each arm with large confidenece intervals that overlapped 1.0. Overall survival was relatively immature and will continue to be followed, with the next analysis expected in 2024.

The rate of grade 3 or 4 adverse events was 33.9% with LuPSMA vs 43.1% without it. 

DISCLOSURE: Dr. Sartor owns stock or has other ownership interests with AbbVie, Cardinal Health, Clarity Pharmaceuticals, Clovis Oncology, GlaxoSmithKline, Eli Lilly, Noria Therapeutics, PSMA Therapeutics, and UnitedHealth Group; has served as a consultant or advisor to Advanced Accelerator Applications, ARTBIO, Astellas Pharma, AstraZeneca, Bavarian Nordic, Bayer, Blue Earth Diagnostics, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis Oncology, Constellation Pharmaceuticals, Dendreon, EMD Serono, Fusion Pharmaceuticals, Isotopen Technologien, Janssen, MacroGenics, Myovant Sciences, Myriad Genetics, Noria Therapeutics, Novartis, Noxopharm, Pfizer, Point Biopharma, Progenics, Ratio, Sanofi, Telix Pharmaceuticals, TeneoBio, and Theragnostics; has received institutional research funding from Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, Constellation Pharmaceuticals, Dendreon, Endocyte, InVitae, Janssen, Lantheus, Merck, Progenics, Sanofi, and SOTIO; has a patent for Saposin C and receptors as targets for treatment of benign and malignant disorders; has provided expert testimony for Sanofi; and has received reimbursement for travel, accommodations, or expenses from AstraZeneca, Bayer, Johnson & Johnson, Progenics, and Sanofi.


1. Sartor AO, Castellano D, Herrmann K, et al: Phase III trial of [177Lu] Lu–PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore). ESMO Congress 2023. Abstract LBA13. Presented October 23, 2023.

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