Adding Radioligand Therapy Pluvicto to SOC Cuts Risk of Prostate Cancer Progression or Death 28%, but How Many Doses?

Combining the radioligand therapy lutetium (177Lu) vipivotide tetraxetan, or 177Lu-PSMA-617, with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitor (ARPI) therapy reduced the risk of progression or death by 28% for patients with prostate-specific membrane antigen–positive (PSMA+) metastatic hormone-sensitive prostate cancer (mHSPC), according to data presented at Sunday’s presidential session of the 50th Congress of the European Society for Medical Oncology, held in Berlin, Germany.1

The radioligand therapy, sold as Pluvicto by Novartis, received FDA approval in March 2025 for patients with metastatic castration-resistant prostate cancer (mCRPC). The therapy is part of a wave of radiopharmaceuticals reaching the market to treat prostate and other cancers, finely pinpointing an agent to bind to markers on specific cancer cells.

The phase 3 PSMAddition trial (NCT04720157) tested 177Lu-PSMA-617 with ARPI and ADT against ARPI and ADT alone, with the latter currently considered the standard of care (SOC). Eligible patients had treatment-naïve or minimally treated mHSPC and at least 1 PSMA lesion. Randomization was 177Lu-PSMA-617 plus ARPI/ADT for 6 cycles or ARPI/ADT alone, with patients stratified by disease volume, age, and previous/planned primary tumor treatment. Control arm patients were allowed to cross over into the treatment arm if eligible.

Scott Tagawa, MD, MS | Image: Weill Cornell

PSMAddition’s primary end point was radiographic progression-free survival (rPFS) with secondary end points being overall survival (OS), overall response rate (ORR), safety and tolerability, and quality of life (QOL). Scott Tagawa, MD, MS, a professor of medicine at Weill Cornell Medicine and a medical oncologist at NewYork-Presbyterian/Weill Cornell Medical Center, presented the results, which were as follows1:

• Combining 177Lu-PSMA-617 with SOC produced statistically significant rPFS, reducing the risk of radiographic progression or death by 28% (HR, 0.72; 95% CI, 0.58-0.90) vs SOC alone in patients with PSMA+ mHSPC
• Results show a positive trend in OS in the treatment arm (HR, 0.84; 95% CI, 0.63-1.13), but data are not yet mature; more patients achieved a complete response vs SOC alone (57.1% vs 42.3%), and the ORR was numerically higher in the treatment arm vs the SOC arm (85.3% vs 80.8%)
• Treatment with 177Lu-PSMA-617 plus SOC delayed time to progression to mCRPC compared with SOC (HR, 0.70; 95% CI, 0.58-0.84)
• The rPFS benefit was consistent across prespecified subgroups
• Nearly all patients in the therapy arm experienced adverse effects, with dry mouth (all grade 1-2) being the most common.

Tagawa interpreted the findings as confirmation that using the radioligand therapy with SOC at the outset was a winning strategy.

“These findings suggest that combining 177Lu-PSMA-617 with standard-of-care hormonal therapy offers patients more time without disease progression, a safety profile with adverse events that are most often low grade and managed with supportive care, and an encouraging trend in overall survival,” he said in a statement.2

However, commentator Arun Azad, MD, dug into the data and wondered if they could have been more robust. He questioned whether the crossover design will allow for clear OS results, and then asked if data showing QOL “was not adversely affected” truly represents a positive result. Would it be better, he asked, to evaluate patients after 2 cycles of the radioligand therapy to see if more cycles are needed for all patients?

Azad said that after 8 months, there is the risk that 177Lu-PSMA-617 can affect other organs, thus adversely impacting QOL.

However, during the presidential session, Tagawa’s remarks said this will be addressed as more data become available.

“I look forward to additional analyses that will break down the individual components of the patient-reported outcomes, as well as the planned secondary and exploratory end points, assessing imaging as well as tumor and blood biomarkers," he said.

Novartis said in its statement that the company plans to submit its application based on this trial to regulatory authorities by the end of the year. Company officials have previously said that an approval based on these data could potentially double the number of patients eligible for treatment with Pluvicto, in combination with ARPI therapy and ADT.2

References

1. Tagawa ST, Sartor O, Piuats JM, et al. Phase III trial of [177 Lu] Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). Presented at: European Society for Medical Oncology; October 17-21, 2025; Berlin, Germany. Abstract LBA6.
2. PSMAddition data show Novartis’ Pluvicto delays progression to end-stage prostate cancer. News release. Novartis. October 19, 2025. Accessed October 19, 2025. https://www.novartis.com/news/media-releases/psmaddition-data-show-novartis-pluvictotm-delays-progression-end-stage-prostate-cancer