SUO 2025: PSMAddition: Top Line Results from a Phase 3 Trial of ADT and ARPI +/- 177Lu-PSMA-617 in Patients with PSMA-Positive mHSPC

(UroToday.com) The 2025 SUO annual meeting featured a prostate cancer session and a late breaking abstract presentation by Dr. Scott Tagawa discussing top line results from PSMAddition, a Phase 3 Trial of ADT and ARPI +/- ¹⁷⁷Lu-PSMA-617 in Patients with PSMA-Positive Metastatic Hormone Sensitive Prostate Cancer. The PSMA-targeted radioligand therapy ¹⁷⁷Lu-PSMA-617 prolongs radiographic progression free survival with a manageable safety profile in patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) in post-taxane (VISION¹) and taxane-naive (PSMAfore²) settings. PSMAddition is the first phase III study of targeted radioligand therapy in patients with mHSPC.

This trial randomized men with untreated or minimally treated mHSPC 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 + androgen receptor pathway inhibitor
• Control arm: ADT + androgen receptor pathway inhibitor
  • Crossover to the ¹⁷⁷Lu-PSMA 617 arm was permitted upon radiographic progression

The primary study endpoint was radiographic progression free survival, assessed via blinded central review using the PCWG3/RECIST v1.1 criteria. The key secondary endpoint was overall survival, with other endpoints including:

• PSA90 response rate
• Time to castration resistance
• Progression free survival 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 represent the second interim analysis of radiographic progression free survival (data maturity: 74.4%) and the first interim analysis of overall survival (data maturity: 47.3%).

Overall, 1,144 patients were randomized 1:1 to the ¹⁷⁷Lu-PSMA 617 + ADT + androgen receptor pathway inhibitor and ADT + androgen receptor pathway inhibitor arms, respectively (n= 572 for each arm). 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 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 radiographic progression free survival significantly prolonged with the addition of ¹⁷⁷Lu-PSMA-617 (HR 0.72, 95% CI 0.58-0.90, p = 0.002). The median radiographic progression free survival has not been reached in either arm yet:

The radiographic progression free survival benefit in favor of ¹⁷⁷Lu-PSMA-617 addition was consistent across all evaluable subgroups:

 The overall survival analysis to date demonstrates a trend towards an overall survival 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:

• Objective response rate: 85% versus 81%
  • Complete response: 57% versus 42%
• Time to PSA progression: HR 0.42, 95% CI 0.30-0.59
• PSA nadir <0.2 ng/ml at 48 weeks: 87% versus 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
• Progression free survival 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% versus 2.1%).  The adverse event profiles were consistent with those of ¹⁷⁷Lu-PSMA 617 and androgen receptor pathway inhibitors. 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 cytopenia 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%

Dr. Tagawa concluded his presentation discussing the PSMAddition trial with the following take home points:

• Combining ¹⁷⁷Lu-PSMA-617 with ADT + androgen receptor pathway inhibitor led to a statistically significant improvement in radiographic progression free survival in patients with PSMA-positive mHSPC, compared to ADT + androgen receptor pathway inhibitor
  • This benefit was consistent across subgroups
  • There was a positive trend in overall survival; 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 + androgen receptor pathway inhibitor
  • 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 + androgen receptor pathway inhibitor provides a
  clinically meaningful benefit in patients with PSMA-positive mHSPC

Presented by: Scott T. Tagawa, MD, MS, FACP, FASCO, Weill Cornell Medicine, New York City, NY

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 Society of Urologic Oncology (SUO) annual meeting held in Phoenix, AZ, between the 2^nd and 5^th of December 2025. 

References:

1. Sartor O, de Bono J, Chi KN et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 16;385(12):1091-1103.
2. Morris MJ, Castellano D, Herrmann K, et al. ¹⁷⁷Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naïve patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): A phase 3, randomized, controlled trial. Lancet 2024 Sep 28;404(10459):1227-1239.