(UroToday.com) The 2025 European Society for Medical Oncology (ESMO) Annual Congress, held in Berlin, Germany, between October 17th and 21st, 2025, was host to a presidential symposium. Dr. Scott Tagawa presented PSMAddition, a phase III trial of [177Lu]Lu-PSMA-617 combined with androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI) in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC).
The PSMA-targeted radioligand therapy 177Lu-PSMA-617 prolongs radiographic progression-free survival (rPFS) with a manageable safety profile in patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) in post-taxane (VISION) and taxane-naive (PSMAfore) settings.1,2 PSMAddition is the first phase III study of targeted radioligand therapy in patients with mHSPC.
This trial randomized men with untreated or minimally treated mHPSC and ≥1 PSMA-positive metastatic lesion on 68Ga-PSMA-11 PET/CT to:
- Experimental arm: 177Lu-PSMA 617 (7.4 GBq ±10% 6 cycles q6w) + ADT + ARPI
- Control arm: ADT + ARPI
- Crossover to the 177Lu-PSMA 617 arm was permitted upon radiographic progression
The primary study endpoint was rPFS, assessed via blinded central review using the PCWG3/RECIST v1.1 criteria. The key secondary endpoint was overall survival (OS), with other endpoints including:
- PSA90 response rate
- Time to castration resistance
- Progression-free survival (PFS) and PFS2
- PSA <0.2 ng/ml at 12, 24, and 38 weeks
- Safety and tolerability
The study cut-off date for this analysis was January 13, 2025. The median study follow-up was 23.6 months. The data presented represents the 2nd interim analysis of rPFS (data maturity: 74.4%) and the 1st interim analysis of OS (data maturity: 47.3%).
The study flow chart is summarized below. Overall, 1,144 patients were randomized 1:1 to the 177Lu-PSMA 617 + ADT + ARPI and ADT + ARPI arms, respectively (n= 572 for each arm). The assigned ARPI was most commonly abiraterone acetate (37.6%), followed by apalutamide (33%) and enzalutamide (22%). Radiographic progressive disease was observed in 19.6% and 26.6% of patients in the experimental and control arms, respectively. Crossover to the 177Lu-PSMA 617 arm was observed in 16% of patients in the control arm. In the experimental arm, 86% of patients received all 6 cycles, and 93% received ≥4 cycles.
The baseline characteristics are summarized below. The median patient age was 68 years. 91% of patients had bone metastases, and 41% had visceral metastases. The median PSA at study entry was 11.9 ng/ml. 68% of patients had high-volume disease, and 50% had de novo mHSPC.
The study met its primary endpoint with rPFS significantly prolonged with the addition of 177Lu-PSMA-617 (HR: 0.72, 95% CI: 0.58-0.90, p=0.002). Median rPFS has not been reached in either arm yet.
The rPFS benefit in favor or 177Lu-PSMA-617 addition was consistent across all evaluable subgroups.
OS analysis to date demonstrates a trend towards an OS benefit in the intervention arm (HR: 0.84, 95% CI: 0.64-1.13, p=0.125):
Other key secondary endpoints similarly favored the intervention arm:
- ORR: 85% vs 81%
- Complete response: 57% vs 42%
- Time to PSA progression: HR=0.42, 95% CI: 0.30-0.59
- PSA nadir <0.2 ng/ml at 48 weeks: 87% vs 75%
- Time to symptomatic skeletal event: HR=0.89, 95% CI: 0.62-1.26
- Time to mCRPC: HR=0.70, 95% CI: 0.58-0.84
- PFS per investigator assessment: HR=0.64, 95% CI: 0.51-0.79
Any adverse event was observed in 98.4% and 96.6% of patients in the experimental and control arms, respectively. Grade ≥3 events were observed in 51% and 43%, respectively. Serious adverse events related to any study treatment were observed in 6.9% and 2.5% of patients, respectively (Grade ≥3: 5.5% vs 2.1%).
The adverse event profiles were consistent with those of 177Lu-PSMA 617 and ARPIs. Dr. Tagawa highlighted the increased incidences of the following any-grade adverse events in the 177Lu-PSMA 617 arm:
- Dry mouth: 46% versus 4%
- Nausea: 34% versus 9%
- Constipation: 18% versus 16%
- Decreased appetite: 14% versus 6.5%
- Vomiting: 14% versus 4%
- Diarrhea: 12% versus 10%
- Dysgeusia: 12% versus 4%
As expected, the frequency of cytopenic events was higher in the 177Lu-PSMA 617 arm:
- Cytopenia: 44% versus 20%
- Anemia: 28% versus 14%
- Neutropenia: 15% versus 4%
- Thrombocytopenia: 11% versus 3%
From a quality-of-life standpoint, there were no significant differences in the BPI-SF pain intensity or FACT-P total scores between the two arms:
Dr. Tagawa concluded as follows:
- Combining 177Lu-PSMA-617 with ADT + ARPI led to a statistically significant improvement in radiographic progression-free survival in patients with PSMA-positive mHSPC, compared to ADT + ARPI
- This benefit was consistent across subgroups
- There was a positive trend in OS; follow-up for mature data is ongoing
- PSA response, progression-free survival, mCRPC, and symptomatic skeletal events results favored the 177Lu-PSMA-617 combination arm
- Safety findings were consistent with the known profile of 177Lu-PSMA-617, with no unexpected concerns about combination with ADT+ARPI
- Adverse events were more frequent in the 177Lu-PSMA-617 combination arm, most commonly dry mouth, fatigue, and nausea
- There were no clinically significant differences in time to worsening in health-related quality of life and pain
- These findings indicate that combining 177Lu-PSMA-617 with ADT + ARPI provides a
clinically meaningful benefit in patients with PSMA-positive mHSPC
Presented by: Scott T. Tagawa, MD, MS, FACP, FASCO, Professor of Medicine and Urology, Weill Cornell Medicine, New York Presbyterian Hospital, New York City, NY
Written by: Rashid K. Sayyid, MD, MSc, Assistant Professor, Urologic Oncologist, Department of Urology at The University of Arizona and Banner University Medical Center – Tucson, AZ, @rksayyid on X during the 2025 European Society for Medical Oncology (ESMO) Annual Congress, Berlin, Germany, October 17–21, 2025
References:- Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021; 385:1091–1103.
- Morris MJ, Hirmand M, Chi KN, et al. PSMAfore: a randomized, phase 3 trial of [177Lu]Lu-PSMA-617 versus a change in androgen receptor pathway inhibitor in taxane-naïve metastatic castration-resistant prostate cancer. Lancet. 2024; 404:1227–1239.