PSMAddition: [177Lu]Lu-PSMA-617 Improves Radiographic PFS in PSMA-Positive mAPMN/S Prostate Cancer

Androgen deprivation therapy combined with an androgen receptor pathway inhibitor is a contemporary standard of care for patients with metastatic hormone-sensitive prostate cancer. The phase 3 PSMAddition trial evaluated whether adding the PSMA-targeted radioligand therapy [177Lu]Lu-PSMA-617 (Pluvicto) could further improve outcomes in patients with PSMA-positive disease.

On August 6, 2026, The Lancet published the study titled “[177Lu]Lu-PSMA-617 in patients with PSMA-positive metastatic androgen pathway modulator-naive/sensitive prostate cancer (PSMAddition): a phase 3 randomised, controlled trial.”

Authors: Scott T. Tagawa, Oliver Sartor, Josep M. Piulats, Fred Saad, Karim Fizazi, Alison Reid, Himisha Beltran, Gero Kramer, Hakim Mahammedi, Matthias Eiber, Shilpa Gupta, Daniel Castellano, Ralph Hauke, Hyun Kim, Cheol Kwak, See Tong Pang, Philippe Barthélémy, Dong Dai, Jae Lyun Lee, Luke Nordquist, Russell Z. Szmulewitz, Paweł Wiechno, Alejandro Yovine, Lauren Smith, Emmanuel Bouillaud, Olga Sakharova, and Michael J. Morris, for the PSMAddition Investigators.

How Does Pluvicto Work?

Pluvicto is a PSMA-targeted radioligand therapy that selectively delivers beta-particle radiation to PSMA-positive cells and the surrounding tumor microenvironment. Lutetium Lu 177 vipivotide tetraxetan combines the radionuclide lutetium-177 with a PSMA-binding ligand. PSMA is a transmembrane protein that is highly expressed on prostate cancer cells.

After binding to PSMA-expressing cells, beta-minus radiation from lutetium-177 delivers radiation to these cells and surrounding cells, inducing DNA damage that can lead to cell death. PSMA is also expressed in some normal tissues. In PSMAddition, the investigators noted that dry mouth was probably associated with normal extra-prostatic PSMA expression.

The PSMAddition Trial

PSMAddition is an ongoing international, randomized, open-label, phase 3 superiority trial conducted at 169 sites across 20 countries. The study enrolled patients with treatment-naive or minimally treated metastatic androgen pathway modulator-naive/sensitive prostate cancer, also known as metastatic hormone-sensitive prostate cancer. Eligible patients were required to have at least one PSMA-positive metastatic lesion on centrally reviewed baseline [68Ga]Ga-PSMA-11 PET imaging.

Between June 15, 2021, and July 25, 2023, 1,529 patients were screened and 1,144 were randomly assigned in a 1:1 ratio to receive [177Lu]Lu-PSMA-617 plus androgen deprivation therapy and an androgen receptor pathway inhibitor or ADT plus ARPI alone.

[177Lu]Lu-PSMA-617 was administered intravenously at 7.4 GBq (200 mCi) ±10% every 6 weeks for up to six cycles. The ARPI was selected by the investigator according to local authorization and could include abiraterone, enzalutamide, apalutamide, darolutamide, or rezvilutamide.

Half of the study population had de novo metastatic disease, while 68% had high-volume disease. The median age was 68 years. The primary endpoint was radiographic progression-free survival assessed by blinded independent central review. Overall survival was the key secondary endpoint.

Radiographic Progression-Free Survival

At the prespecified interim analysis, with a data cutoff of January 13, 2025, 139 of 572 patients in the [177Lu]Lu-PSMA-617 group and 172 of 572 patients in the control group had experienced radiographic progression or death.

Adding [177Lu]Lu-PSMA-617 significantly improved radiographic progression-free survival, corresponding to a 28% reduction in the relative risk of radiographic progression or death compared with ADT plus ARPI alone.

The hazard ratio was 0.72 (95% CI 0.58–0.90; p=0.0021), meeting the trial’s primary endpoint. Median radiographic progression-free survival had not been reached in either treatment group.

The benefit was generally consistent across sensitivity and subgroup analyses, including patients with high- versus low-volume disease and those with de novo versus recurrent metastatic disease.

Overall Survival Remains Immature

At this interim analysis, there was no statistically significant difference in overall survival between the two groups.

A total of 85 patients in the [177Lu]Lu-PSMA-617 group and 99 patients in the control group had died, resulting in an overall survival hazard ratio of 0.84 (95% CI 0.63–1.13; p=0.13). Median overall survival had not been reached in either arm.

The investigators noted that overall survival data remained immature. Crossover was permitted after centrally confirmed radiographic progression, and by the data cutoff, 91 patients in the control group had crossed over to receive [177Lu]Lu-PSMA-617.

Deeper PSA and Tumor Responses

Several secondary efficacy measures also favored the [177Lu]Lu-PSMA-617 combination.

Time to PSA progression was prolonged with [177Lu]Lu-PSMA-617, with a hazard ratio of 0.42 (95% CI 0.30–0.59). Time to development of metastatic androgen pathway modulator-resistant prostate cancer was also prolonged, with a hazard ratio of 0.70 (95% CI 0.58–0.84).

Among patients with measurable soft-tissue disease at baseline, accounting for bone lesion progression, the objective response rate was 85% with [177Lu]Lu-PSMA-617 plus ADT and ARPI compared with 81% with ADT plus ARPI alone.

Complete responses occurred in 57% and 42% of patients, respectively. PSA90 response rates and the proportion of patients achieving a PSA nadir below 0.2 ng/mL were also higher with [177Lu]Lu-PSMA-617 at weeks 12, 24, and 48.

Safety Profile

Adverse events occurred in 98% of patients receiving [177Lu]Lu-PSMA-617 plus ADT and ARPI and 97% of those receiving ADT plus ARPI alone. Grade 3 or higher adverse events were reported in 51% and 43% of patients, respectively. Serious adverse events occurred in 32% of patients in the [177Lu]Lu-PSMA-617 group and 29% in the control group.

Dry mouth was the most common adverse event with [177Lu]Lu-PSMA-617, occurring in 46% of patients compared with 4% in the control group. All dry mouth events were grade 1 or 2, and none were serious. Other adverse events occurring more frequently with [177Lu]Lu-PSMA-617 included nausea, anemia, decreased appetite, vomiting, dysgeusia, decreased white blood cell counts, and decreased lymphocyte counts.

Cytopenia-related adverse events occurred in 44% of patients receiving [177Lu]Lu-PSMA-617 compared with 20% in the control group, with grade 3 or higher events reported in 14% and 5%, respectively. Fatal adverse events occurred in 3% and 2% of patients, respectively, and none were considered related to study treatment. The investigators reported no unexpected safety findings associated with combining [177Lu]Lu-PSMA-617 with ADT plus ARPI.

Patient-Reported Outcomes

Patient-reported outcomes showed a more nuanced picture. For the composite endpoints incorporating worsening quality of life or pain, clinical progression, or death, hazard ratios were above 1.0 but below 1.2, with confidence intervals that included 1.0.

Longitudinal analyses showed modest worsening in both groups. FACT-P total scores worsened more during the [177Lu]Lu-PSMA-617 treatment period through week 36, while differences between the groups were nominal thereafter through week 108. Longitudinal changes in EQ-5D-5L utility and pain intensity were comparable between treatment groups.

The authors noted that detailed patient-reported outcome analyses will be reported separately.

FDA Approval of Pluvicto in This Setting

On July 31, 2026, the US Food and Drug Administration approved lutetium Lu 177 vipivotide tetraxetan (Pluvicto) in combination with an androgen receptor pathway inhibitor for adults with PSMA-positive metastatic androgen pathway modulation-naive or -sensitive prostate cancer.

The approval was supported by results from the phase 3 PSMAddition trial. This disease setting was previously referred to as metastatic hormone-sensitive prostate cancer. Patients should be selected for treatment based on PSMA expression using Locametz, which contains gallium Ga 68 gozetotide, or another FDA-approved PSMA PET product.

The recommended dose of lutetium Lu 177 vipivotide tetraxetan is 7.4 GBq (200 mCi) intravenously every 6 weeks for six doses, or until disease progression or unacceptable toxicity. In PSMAddition, patients received a gonadotropin-releasing hormone agonist or antagonist concurrently or had undergone bilateral orchiectomy.

What the Findings Mean

PSMAddition is the first phase 3 trial of a targeted radionuclide therapy in metastatic androgen pathway modulator-naive/sensitive prostate cancer.

At the current interim analysis, adding [177Lu]Lu-PSMA-617 to ADT plus ARPI significantly prolonged radiographic progression-free survival in patients with PSMA-positive disease, while also producing deeper PSA responses and delaying progression to metastatic androgen pathway modulator-resistant prostate cancer.

However, overall survival remains immature, and no statistically significant survival difference has yet been demonstrated. The investigators also noted that crossover from the control group after radiographic progression could complicate interpretation of future overall survival analyses.

Longer follow-up is also important for safety, particularly because renal and bone marrow events often occur late in targeted radionuclide therapy and might not have been captured within the current follow-up period.

The authors concluded that the interim findings support [177Lu]Lu-PSMA-617 plus ADT and ARPI as a potential new treatment option for patients with PSMA-positive metastatic androgen pathway modulator-naive/sensitive prostate cancer, with final radiographic progression-free survival, overall survival, and updated safety analyses still planned.

The full article is available in The Lancet.