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In men with newly diagnosed metastatic hormone-sensitive prostate cancer, adding lutetium-177 PSMA-617 (¹⁷⁷Lu-PSMA-617) to standard hormone therapy led to a statistically significant improvement in radiographic progression-free survival (PFS) compared with standard hormone therapy alone.

Despite immature overall survival data, the results “support the clinical benefit of early addition of ¹⁷⁷Lu-PSMA-617 to the backbone of androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI),” said investigator Scott Tagawa, MD, medical oncologist at NewYork-Presbyterian/Weill Cornell Medical Center, New York City, who presented the findings at European Society for Medical Oncology (ESMO) Annual Meeting 2025.

Overall, “we’re seeing benefits consistent with prior trials in later disease stages, but now brought forward to the frontline,” Tagawa said.

However, study discussant Arun Azad, MBBS, PhD, medical oncologist, Peter MacCallum Cancer Center, University of Melbourne, Melbourne, Australia, isn’t convinced — at least not yet.

Despite the significant radiographic PFS benefit, Azad said he would not recommend widespread use of ¹⁷⁷Lu-PSMA-617 in the first-line setting at this stage, given the immature overall survival data and the higher rates of adverse events.

“The goal of any anti-cancer treatment I give to patients is to help them live longer and live better. This goal has not been achieved in PSMAddition,” Azad said.

¹⁷⁷Lu-PSMA-617 (Pluvicto, Novartis) is currently FDA approved for use either before or after taxane-based chemotherapy in PSMA-positive metastatic castration-resistant prostate cancer. These approvals were based on trials demonstrating that ¹⁷⁷Lu-PSMA-617 led to an overall survival and radiographic PFS benefit in men with prior exposure to an ARPI and taxane-based chemotherapy as well as a radiographic PFS benefit in taxane-naive patients who had progressed on an ARPI.

The current study marks the first randomized phase 3 trial of a targeted radioligand therapy in newly-diagnosed metastatic hormone-sensitive prostate cancer.

The trial enrolled 1144 patients who were untreated or minimally treated (0-45 days of hormonal therapy prior to signing consent), had an Eastern Cooperative Oncology Group Performance status of 0-2, and had PSMA-positive disease.

Participants were randomly allocated (1:1) to receive ADT plus an ARPI (physician’s choice of abiraterone, enzalutamide, apalutamide, or darolutamide) with or without ¹⁷⁷Lu-PSMA-617 administered at 7.4 GBq every 6 weeks for up to 6 cycles. Patients in the control group could cross over to receive ¹⁷⁷Lu-PSMA-617 upon confirmed radiographic progression.

At a median follow-up of 23.6 months, the trial met the primary endpoint of radiographic PFS. The addition of ¹⁷⁷Lu-PSMA-617 to standard of care resulted in a 28% reduction in the risk for radiographic progression or death (hazard ratio [HR], 0.72; P = .002), surpassing the prespecified statistical threshold.

The radiographic PFS benefit “was consistent across all subgroups, including tumor volume and disease presentation,” Tagawa said.

The overall survival data remain immature. At the first preplanned interim analysis for overall survival, the HR favored the ¹⁷⁷Lu-PSMA-617 group, although the CIs crossed 1 (HR, 084; 95% CI, 0.63-1.13), Tagawa reported.

Additional efficacy endpoints also favored the lutetium group, including prostate-specific antigen (PSA) nadir < 0.2 ng/mL at 48 weeks (87% vs 75%), time to PSA progression (HR, 0.42), time to metastatic castration-resistant prostate cancer (HR, 0.70), and time to symptomatic skeletal event (HR, 0.89).

As expected, adverse events were much more common with the addition of lutetium — 89.4% vs 69.7% without lutetium for any grade event related to a study treatment. Grade 3 or higher adverse events were also higher in the lutetium group — 22.7% vs 12.2%.

Most adverse events were grade 1 or 2 dry mouth, fatigue, dry eye and nausea. More cytopenias occurred with lutetium, including anemia, neutropenia, and thrombocytopenia, but most were low grade.

Overall, there were no significant differences between groups in time to worsening pain or health-related quality of life, but patients receiving ¹⁷⁷Lu-PSMA-617 had a numerically shorter time to worsening quality of life — median of 11.33 months vs 17.12 months (HR, 1.14; 95% CI, 0.98-1.33).

Azad posed several questions about the drug’s use in the first-line setting in this patient population.

“The first one is whether it will actually lead to improved overall survival,” Azad said.

Additionally, patients receiving ¹⁷⁷Lu-PSMA-617 had many more adverse events. Although most adverse events were low-grade, chronic grade 1-2 toxicities can still erode daily functioning, he said.

“It’s good that there was very little, if any, grade 3 or higher dry mouth or GI [gastrointestinal] toxicity. But it’s been our experience using ¹⁷⁷Lu-PSMA-617 over many years that chronic grade 1-2 dry mouth and GI toxicity can actually impair patients’ quality of life,” he explained.

Azad also noted that the shorter median time to deterioration in quality-of-life in the lutetium arm suggests a subtle but persistent decline that began around the time most patients had completed their treatment course.

It will be important to optimize patient selection and identify patients with metastatic hormone-sensitive prostate cancer who are more likely to benefit from upfront ¹⁷⁷Lu-PSMA-617, he said.

“We’re definitely moving into an era of personalized medicine,” he added. Although ¹⁷⁷Lu-PSMA-617 was used in a very broad population in this study, “we have to remember it’s a targeted therapy as well. We need to harness its target, PSMA, to better identify predictive biomarkers and use this treatment better.” 

This study was funded by Novartis. Tagawa and Azad disclosed relationships with Novartis and other pharmaceutical companies.