PSMAddition: Adding 177Lu-PSMA-617 to ADT plus ARPI extends rPFS in mHSPC

Adding ¹⁷⁷Lu-PSMA-617 (lutetium (177Lu) vipivotide tetraxetan;Pluvicto) to the backbone of androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARPI) significantly improved radiographic progression-free survival (rPFS) in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC), according to data from the phase 3 PSMAddition trial (NCT04720157).¹

The results were presented by Scott T. Tagawa, MD, MS, FACP, FASCO, of Weill Cornell Medicine, at the 2025 European Society for Medical Oncology Congress in Berlin, Germany.

“¹⁷⁷Lu-PSMA-617 has demonstrated an overall survival and radiographic progression-free survival benefit in patients with prior exposure to ARPI and taxane chemotherapy in the VISION study and an rPFS benefit in those post-ARPI but naïve to chemotherapy for metastatic disease in the PSMAfore study,” Tagawa explained during the presentation. “The PSMAddition study represents the first phase 3 study of any targeted radionuclide therapy in patients with metastatic hormone-naïve prostate cancer.”

In total, the PSMAddition trial enrolled 1144 patients who were randomly assigned to receive 7.4 GBq +/- 10% ¹⁷⁷Lu-PSMA-617 for 6 cycles plus ADT and ARPI (n = 572) or to ADT and ARPI alone (n = 572). Patients were eligible for enrollment If they had untreated or minimally treated mHSPC, an ECOG performance status of 0 to 2, at least 1 PSMA-positive metastatic lesion per ⁶⁸Ga-PSMA-11 PET/CT imaging, and were appropriate for ADT plus ARPI.

Baseline characteristics were balanced between both arms. The primary end point was rPFS, with overall survival (OS) as a key secondary end point. Other end points included ovjective response rate (ORR), time to metastatic castration-resistant prostate cancer (mCRPC), progression-free survival (PFS), quality of life, and safety.

At a median follow-up of 23.6 months, the primary end point of the study was met, with data showing a statistically significant improvement in rPFS favoring the ¹⁷⁷Lu-PSMA-617 arm (HR, 0.72; 95% CI, 0.58 to 0.90; P = .002). The median rPFS has not been reached in either arm.

The observed benefit in rPFS was consistent across subgroups.

OS data were immature at the time of data report. However, there was a trend toward improvement in the ¹⁷⁷Lu-PSMA-617 arm, though the difference did not achieve statistical significance (HR, 0.84; 95% CI, 0.63 to 1.13; P = .125).

Further, ORR per RECIST v1.1 was 85.3% (95% CI, 79.9% to 89.6) in the ¹⁷⁷Lu-PSMA-617 arm vs 80.8% (95% CI, 74.8 to 85.8) in the comparator arm. Complete responses were achieved in 57.1% and 42.3% of patients, respectively.

Further, more patients in the ¹⁷⁷Lu-PSMA-617 arm achieved a PSA nadir of less than 0.2 ng/mL at 48 weeks, with a rate of 87.4% (95% CI, 83.6 to 90.6) in the ¹⁷⁷Lu-PSMA-617 arm vs 74.9% (95% CI, 70.3 to 79.1) in the comparator arm.

All other secondary end points also favored the ¹⁷⁷Lu-PSMA-617 arm, including time to PSA progression (HR, 0.42; 95% CI, 0.30 to 0.59); time to symptomatic skeletal event (HR, 0.89; 95% CI, 0.62 to 1.26); time to mCRPC (HR, 0.70; 95% CI, 0.58 to 0.84), and PFS per investigator assessment (HR, 0.64; 95% CI, 0.51 to 0.79).

Regarding safety, grade 3 or higher adverse events (AEs) were reported in 50.7% of patients in the ¹⁷⁷Lu-PSMA-617 arm and 43% of patients in the comparator arm. The most common all-grade AEs in the treatment arm were dry mouth (45.7%), fatigue (34.8%), nausea (34.2%), hot flush (29.1%), and anemia (27.1%).

Tagawa also added during the presentation, “There were more cytopenias in the ¹⁷⁷Lu-PSMA-617 treated group, including anemia, neutropenia, and thrombocytopenia. Fortunately, the majority of those were low grade in nature.”

Despite the higher incidence of AEs with ¹⁷⁷Lu-PSMA-617, there did not appear to be a significant difference in quality of life between the study arms, as assessed by time to worsening in BPI-SF pain intensity (HR, 1.02; 95% CI, 0.87 to 1.18) and FACT-P total score (HR, 1.14; 95% CI, 0.98 to 1.33).

Tagawa noted that future analyses will include a break-down of the individual components of patient-reported outcomes as well as tumor and blood biomarkers. According to a news release from Novartis, the company plans to submit these data to regulatory authorities before end of year.²

Tagawa concluded, “Taken together, these findings support the clinical benefit of the early addition of ¹⁷⁷Lu-PSMA-617 to the backbone of ADT and ARPI.”

REFERENCES

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). Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA6. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA6.html.pdf

2. PSMAddition data show Novartis Pluvicto™ delays progression to end-stage prostate cancer. News release. Novartis. October 19, 2025. Accessed November 3, 2025. https://www.novartis.com/news/media-releases/psmaddition-data-show-novartis-pluvictotm-delays-progression-end-stage-prostate-cancer