The addition of lutetium-177–labeled PSMA-617 (vipivotide tetraxetan; 177Lu-PSMA-617), a targeted radionuclide therapy, to standard-of-care androgen-deprivation therapy and an androgen receptor pathway inhibitor appeared to significantly improve radiographic progression–free survival in patients with prostate-specific membrane antigen (PSMA)-positive metastatic hormone-naive prostate cancer. Presented during the European Society for Medical Oncology (ESMO) Congress 2025, these results mark the first time a targeted radionuclide therapy has demonstrated benefit in this patient population, suggesting a potential paradigm shift in early-line treatment strategies.1
The phase III PSMAddition trial met its primary endpoint, showing a statistically significant improvement in radiographic progression–free survival with the combination (P = .002), which was consistent across various patient subgroups. Although overall survival data are still maturing, a positive trend was observed, and the treatment appeared to be associated with a safety profile that was predominantly low grade without detrimentally impacting patients’ quality of life.
“The addition of 177Lu-PSMA-617 to standard-of-care androgen-deprivation therapy plus an androgen receptor pathway inhibitor resulted in a 28% improvement in radiographic [disease] progression or death, which was statistically significant based on the preplanned analysis design,” said presenting author Scott T. Tagawa, MD,MS, FACP, FASCO, Professor of Medicine and Urology at Weill Cornell Medicine in New York City. “Taken together, these findings support the clinical benefit of the early addition of 177Lu-PSMA-617 to the backbone of androgen-deprivation therapy plus an androgen receptor pathway inhibitor.”
Scott T. Tagawa, MD,MS, FACP, FASCO
As Dr. Tagawa explained, metastatic hormone-naive prostate cancer is a challenging disease where, despite androgen-deprivation therapy and androgen receptor pathway inhibitors being standard of care, outcomes remain suboptimal, and patients are at risk for disease progression. 177Lu-PSMA-617 is a targeted radionuclide therapy that delivers targeted radiation to PSMA-expressing cancer cells.
Previous studies (VISION, PSMAfore) have demonstrated its efficacy in later lines of treatment for metastatic hormone-resistant prostate cancer. The PSMAddition study represents the first phase III investigation of any targeted radionuclide therapy in the metastatic hormone-naive prostate cancer setting, exploring its utility as an upfront intensification strategy.
Study Methods
The PSMAddition study was a global, randomized, open-label phase III trial. Eligible adult patients had treatment-naive or minimally treated (≤ 45 days of hormonal therapy) metastatic hormone-naive prostate cancer, an Eastern Cooperative Oncology Group performance status score of 0 to 2, and confirmed PSMA-positive metastatic lesions on a [68Ga]Ga-PSMA-11 PET/CT scan (defined as at least one lesion with uptake greater than liver).
Patients were randomly assigned in a 1:1 ratio to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks for up to six cycles) combined with androgen-deprivation therapy plus an androgen receptor pathway inhibitor of the physician’s choice (177Lu-PSMA-617 arm) or androgen-deprivation therapy plus an androgen receptor pathway inhibitor alone with the option to crossover to receive 177Lu-PSMA-617 at confirmed radiographic progression (control arm). Stratification factors included disease volume (high/low), age, and androgen receptor pathway inhibitor choice.
The primary endpoint was radiographic progression–free survival, defined by radiographic disease progression (per centrally assessed PCWG3 RECIST 1.1 criteria) or death. Key secondary endpoints included overall survival, objective response rate, safety/tolerability, and patient reported quality of life.
The presented data represent interim analysis 2 for radiographic progression–free survival (the first efficacy interim analysis) and the first planned interim analysis for overall survival, with a median study follow-up of 23.6 months. Patients in the control arm with confirmed radiographic disease progression were allowed to cross over to receive 177Lu-PSMA-617 on study.
A total of 1,144 patients were randomized (50.0% with de novo metastatic hormone-naive prostate cancer; 68.1% with high-volume disease on CT/bone scan). Baseline characteristics were well balanced between the arms, including a median age of 68 years, most patients having bone metastases, high Gleason scores, and high tumor volume by CHAARTED/LATITUDE criteria. Abiraterone was the most common androgen receptor pathway inhibitor used.
Of the 152 patients in the control arm with centrally confirmed radiographic disease progression, 59.9% crossed over to receive 177Lu-PSMA-617, representing approximately 16% of the overall control arm intention-to-treat population.
Significant Improvement in Radiographic Progression–Free Survival
As Dr. Tagawa reported, the primary endpoint was met, with the addition of 177Lu-PSMA-617 to androgen-deprivation therapy plus an androgen receptor pathway inhibitor significantly improving radiographic progression–free survival (hazard ratio [HR] = 0.72; P = .002).
“The radiographic progression–free survival benefit was consistent across all predefined subgroups, including high vs low disease volume and de novo vs recurrent disease,” said Dr. Tagawa.
At this first interim analysis for overall survival, the data are still immature. However, a positive trend favoring early 177Lu-PSMA-617 was observed, with a hazard ratio (HR = 0.84) whose confidence interval currently crosses one. Other secondary efficacy endpoints also appeared to favor 177Lu-PSMA-617, including time to symptomatic skeletal events, time to hormonal resistance, and investigator-assessed progression-free survival.
Patients who began the study with RECIST measurable disease in the 177Lu-PSMA-617 arm also showed higher objective response rates, including complete responses. More patients achieved a prostate-specific antigen (PSA) level of less than 0.2 ng/mL at all prespecified time points in the 177Lu-PSMA-617 arm.
The overall incidence of adverse events was reported to be slightly higher with the addition of 177Lu-PSMA-617, including more serious adverse events. However, no treatment-related adverse events led to death in either arm. The safety findings were found to be consistent with the known profiles of all study components.
Dry mouth was the most common adverse event, with 46% of patients in the 177Lu-PSMA-617 arm reporting grade 1 (41%) to 2 (5%) events, as compared with 3.4% in the control arm. Fatigue and gastrointestinal toxicity was also more common in the 177Lu-PSMA617 arm.
Composite grade 3 or higher cytopenias (anemia, neutropenia, thrombocytopenia) were more frequent with added 177Lu-PSMA-617 (14.4% vs 5.0%), said Dr. Tagawa, but the majority were low-grade.
“Despite the increased incidence of adverse events, there was no meaningful difference in patient-reported outcomes, indicating that quality of life was not adversely affected,” said Dr. Tagawa.
“These findings support the clinical benefit of integrating 177Lu-PSMA-617 earlier into the treatment paradigm for metastatic hormone-naive prostate cancer,” Dr. Tagawa concluded.
DISCLOSURE: Dr. Tagawa reported financial interests with Lilly, Convergent Therapeutics, Ambrx, Telix Pharmaceuticals, Blue Earth Diagnostics, POINT Biopharma, Myovant, Bayer, 4D Pharma, Gilead, Pfizer, Janssen, Astellas, AbbVie, Novartis, Seagen, Clarity, Merck, EMD Serono, Regeneron, Daiichi Sankyo, General Electric, Abdera, AIkido Pharma, Boston Scientific, and Promontory.
REFERENCE
1. Tagawa ST, Sartor O, Piulats JM, et al: Phase 3 trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). ESMO Congress 2025. Abstract LBA6. Presented October 19, 2025.
EXPERT POINT OF VIEW
Invited discussant Arun Azad, MBBS, PhD, FRACP, Medical Oncologist and Translational Researcher at Peter MacCallum Cancer Centre in Melbourne, Australia, acknowledged the significance of the PSMAddition trial as the “first randomized phase III evidence of lutetium PSMA [therapy] in metastatic hormone-[naive] prostate cancer” but raised several critical concerns about its broad applicability.
Dr. Azad noted several of the study’s strengths, including its large, randomized design with an active control arm, and confirmed that the primary endpoint of radiographic progression–free survival was met by the experimental treatment. However, he questioned whether lutetium-177–labeled PSMA-617 (vipivotide tetraxetan; 177Lu-PSMA-617) is “ready for prime time in metastatic hormone-[naive] prostate cancer” without addressing several key issues.
Arun Azad, MBBS, PhD, FRACP
Dr. Azad’s primary concern was the lack of an overall survival benefit at the first interim analysis. He postulated that because of the trial’s crossover design, overall survival benefit would likely be diluted with longer follow-up, drawing parallels to metastatic hormone-resistant prostate cancer trials (PSMAfore, PR21) where early 177Lu-PSMA-617 use was not found to improve overall survival.
Dr. Azad advocated for optimizing patient selection using biomarkers, despite PSMAddition showing radiographic progression–free survival benefit across all subgroups. He emphasized that 177Lu-PSMA-617 is a targeted therapy, and that leveraging quantitative prostate-specific membrane antigen (PSMA) biomarkers—such as PSMA SUVmean, as used in studies like VISION—may help identify patients who truly benefit from higher tumor radiation delivery. He presented dosimetry data illustrating how patients with low PSMA uptake receive significantly less radiation to their tumors and more to normal tissues, suggesting that some patients might be “overtreated.”
Dr. Azad challenged the fixed six-cycle treatment duration, proposing that a PSMA PET scan after two to four cycles should guide treatment discontinuation for patients with complete metabolic responses. Overtreatment, he argued, leads to the “sink effect,” in which patients with low disease burden absorb more 177Lu-PSMA-617 in normal organs such as the salivary glands, resulting in increased toxicity without added benefit.
Regarding toxicity, Dr. Azad highlighted that although severe adverse events were uncommon, chronic grade 1 and 2 dry mouth and gastrointestinal toxicities could still impair quality of life. He also expressed concern about long-term toxicities observed in metastatic hormone-resistant prostate cancer, including secondary myeloid neoplasms and renal impairment, noting that in the 177Lu-PSMA-617 arm of PSMAddition—even with short follow-up—there was a twofold increase in grade 3 or higher second primary cancers and renal events.
“The PSMAddition’s goal to make patients ‘live longer and live better’ was not achieved,” Dr. Azad concluded. “I would not recommend widespread use of 177Lu-PSMA-617 in metastatic hormone-[naive] prostate cancer at this stage but would reserve it for patients with ‘bad’ disease or ‘bad’ scans.”
“Delivering the best outcomes in metastatic hormone-[naive] prostate cancer will take a patient-centered approach focused on identifying predictive biomarkers, avoiding overtreatment, and minimizing late toxicities,” he added.
DISCLOSURE: Dr. Azad reported financial relationships with Aculeus Therapeutics, Amgen, Arvinas, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Noxopharm, Pfizer, Sanofi, Telix, Tolmar, HiNova, Aptevo Therapeutics, Bionomics, Eli Lilly, Exelixis, Gilead Sciences, GlaxoSmithKline, MedImmune, Sanofi-Aventis, and Synthorx.
