Lu-PSMA-617 combined with ADT and ARPI reduced radiographic progression risk by 28%New Treatment Options for Men with Advanced Prostate Cancer

Lancet (London, England) Published August 31, 2026 Study authors: Tagawa Scott T, Sartor Oliver, Piulats Josep M, Saad Fred, Fizazi Karim, Reid Alison, Beltran Himish… PubMed ↗ NCT04720157 ↗ DOI ↗ Editorial oversight: Dr. Julia Lee, PhD · Oncology, Genomics & Drug Development

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Key Takeaway

Note that Lu-PSMA-617 plus ADT and ARPI reduced the risk of radiographic progression by 28% in PSMA-positive patients.

This Phase 3 randomized controlled trial evaluated the efficacy of Lu-PSMA-617 in patients with PSMA-positive metastatic androgen pathway modulator-naive/sensitive (APMN/S) prostate cancer. The study enrolled a large cohort of 1144 patients across 169 sites in 20 countries. The primary objective was to assess radiographic progression-free survival, which was centrally assessed according to the Prostate Cancer Clinical Trials Working Group 3-modified RECIST 1.1 criteria or death.

The study population consisted of men with advanced prostate cancer who were both PSMA-positive and had not yet progressed on androgen pathway modulators. Patients were randomized to receive either Lu-PSMA-617 in combination with androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARPI), or a control regimen consisting of ADT plus ARPI. The Lu-PSMA-617 dose was 7.4 GBq (200 mCi) plus or minus 10% administered every 6 weeks for up to six cycles.

In the primary outcome of radiographic progression-free survival, the Lu-PSMA-617 arm demonstrated a significant improvement over the control arm. Specifically, radiographic progression or death occurred in 24% of the Lu-PSMA-617 group (139/572) compared to 30% of the control group (172/572). This resulted in a 28% reduction in the relative risk of radiographic progression or death. The statistical analysis yielded a hazard ratio (HR) of 0.72 with a 95% confidence interval (CI) of 0.58-0.90 and a p-value of 0.0021. The median radiographic progression-free survival follow-up time was 19.6 months.

Secondary outcomes focused on the safety and tolerability of the treatment regimens. In the Lu-PSMA-617 arm, 51% (286/564) of patients experienced Grade 3 or worse adverse events, compared to 43% (243/565) in the control arm. The most common adverse event was dry mouth, which occurred in 46% of the Lu-PSMA-617 group versus 4% in the control group. Serious adverse events were reported in 32% (180/564) of the Lu-PSMA-617 arm and 29% (162/565) of the control arm. Notably, only 3% (17/564) of the serious adverse events in the Lu-PSMA-617 arm were specifically attributed to the Lu-PSMA-617 medication. No unexpected safety findings were associated with the drug combination.

These results provide a significant data point for the management of PSMA-positive metastatic prostate cancer. The trial confirms that the addition of Lu-PSMA-617 to the standard of care (ADT plus ARPI) provides a statistically significant reduction in the risk of progression. However, clinicians must note that these results are from a second interim analysis of an ongoing study, which may impact the final interpretation of the trial's ultimate conclusions.

Methodological limitations include the fact that this is an interim analysis of an ongoing trial, which may affect the stability of the hazard ratio and p-values as more data are collected. Additionally, the study was funded by Novartis, which may introduce potential bias. The primary focus of the study was radiographic progression, which may differ from other clinical endpoints like overall survival. For clinical practice, these results suggest that combining Lu-PSMA-617 with ADT and ARPI is a viable strategy to extend radiographic progression-free survival in patients with PSMA-positive metastatic APMN/S prostate cancer. Questions remain regarding the long-term durability of this response and the impact on overall survival compared to standard-of-care regimens alone.

How this fits prior evidence

How this fits prior evidence: This finding addresses a gap in the management of PSMA-positive metastatic androgen pathway modulator-naive/sensitive prostate cancer by providing a specific combination therapy. It does not directly relate to the previously reported findings regarding DLL3-directed therapy in neuroendocrine cases, lead-in ADT for neutropenia reduction, salvage radiotherapy for biochemical progression, or Surfactant protein D as a biomarker.

Doctors are looking for better ways to treat advanced prostate cancer that has spread to other parts of the body. For many men, standard hormone therapy is the first line of defense. However, some patients need more powerful treatments when the cancer continues to grow or spread despite these standard medications. This study looked at a new way to combine treatments to give patients more time with stable disease.

The study involved over 1,100 men with a specific type of prostate cancer that shows a certain protein called PSMA. These patients were split into two groups. One group received the standard hormone therapy plus a new drug. The other group received the standard hormone therapy plus a radioactive treatment called Lu-PSMA-617. The goal was to see if adding the radioactive treatment would help keep the cancer from progressing.

The results showed that men who received the radioactive treatment along with their standard care had a better outcome. Specifically, the group receiving the extra treatment had a lower chance of their cancer growing or worsening compared to the group that only received the standard treatment. This means the combination therapy helped keep the cancer stable for a longer period of time for many patients in the study.

Safety is always a major concern when starting new treatments. The study tracked side effects closely for both groups. While the radioactive treatment did cause some more frequent issues like dry mouth, the overall safety profile was manageable for the patients. Most of the serious side effects were not directly caused by the new drug, but rather by the underlying cancer or other factors.

It is important to remember that this study is still ongoing and is currently in its second check-in. While the results are very encouraging for patients with this specific type of prostate cancer, doctors will continue to monitor the data as more patients complete their treatment cycles. This combination could offer a helpful new path for men who need more than just standard hormone therapy.

What this means for you:

Adding a radioactive treatment to standard hormone therapy can help slow the growth of certain prostate cancers.

Study Details

Study typeRct

Sample sizen = 572

EvidenceLevel 2

Follow-up1.4 mo

PublishedAug 2026

PMID42561994

TrialNCT04720157

View Original Abstract ↓

BACKGROUND: A contemporary standard of care for patients with metastatic androgen pathway modulator-naive/sensitive (APMN/S) prostate cancer (also known as metastatic hormone-sensitive prostate cancer) is androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI) until progression. PSMAddition aimed to evaluate the efficacy and safety of [Lu]Lu-PSMA-617 (Lu-PSMA-617) combined with ADT plus ARPI in prostate-specific membrane antigen (PSMA)-positive metastatic APMN/S prostate cancer. METHODS: PSMAddition is an ongoing, randomised, controlled, phase 3 superiority trial conducted at 169 sites across 20 countries, including hospitals, medical centres, and specialist cancer centres. Eligible male patients had treatment-naive or minimally treated metastatic APMN/S prostate cancer diagnosed by CT, MRI, or bone scan and one or more PSMA-positive metastatic lesion on centrally read baseline [Ga]Ga-PSMA-11 PET. Patients were randomly assigned 1:1 to open-label, intravenous Lu-PSMA-617 (7·4 GBq [200 mCi] ±10% every 6 weeks for up to six cycles) with ADT plus ARPI (Lu-PSMA-617 arm) or ADT plus ARPI (control arm). ADT and ARPI were investigator-chosen according to local authorisation and administered per local product labelling. Control arm patients with centrally confirmed radiographic progression could cross over to Lu-PSMA-617. The primary endpoint was radiographic progression-free survival (centrally assessed per Prostate Cancer Clinical Trials Working Group 3-modified RECIST 1.1 or death); secondary endpoints included safety and tolerability. We report the second interim analysis of radiographic progression-free survival in the intention-to-treat population (all randomly assigned participants; data cutoff Jan 13, 2025). Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04720157, and is ongoing. FINDINGS: From June 15, 2021, to July 25, 2023, 1529 patients were screened and 1144 were randomly assigned (n=572 per arm; 1144 [100%] male, 572 [50%] with de novo metastatic APMN/S prostate cancer, 779 [68%] with high-volume disease; median age 68·0 years [IQR 62·0-73·0]). Baseline characteristics were balanced between arms. At second interim analysis for radiographic progression-free survival (median time from randomisation to data cutoff 23·6 months [IQR 20·3-29·2]; median radiographic progression-free survival follow-up time 19·6 months [IQR 14·0-24·1]), 139 (24%) of 572 participants in the Lu-PSMA-617 arm and 172 (30%) of 572 participants in the control arm had radiographic disease progression or death. Radiographic progression-free survival was significantly improved in the Lu-PSMA-617 arm versus the control arm, with a 28% reduction in the relative risk of radiographic progression or death (HR 0·72 [95% CI 0·58-0·90]; p=0·0021; median radiographic progression-free survival not reached in either arm). The primary endpoint was thus met. Grade 3 or worse adverse events occurred in 286 (51%) of 564 patients in the Lu-PSMA-617 arm and 243 (43%) of 565 patients in the control arm. Serious adverse events occurred in 180 (32%) of 564 patients in the Lu-PSMA-617 arm and 162 (29%) of 565 in the control arm; of which 17 (3%) in the Lu-PSMA-617 arm were Lu-PSMA-617-related. The most common adverse event was dry mouth, in 258 (46%) patients in the Lu-PSMA-617 arm and 21 (4%) patients in the control arm; all were grade 1 or 2 and none were serious. Other common adverse events with higher incidence in the Lu-PSMA-617 arm included cytopenias and gastrointestinal disturbances. INTERPRETATION: Combining Lu-PSMA-617 with ADT plus ARPI prolonged radiographic progression-free survival in patients with PSMA-positive metastatic APMN/S prostate cancer. Although adverse events were more frequent, there were no unexpected safety findings associated with the drug combination. Therefore, combining Lu-PSMA-617 with ADT plus ARPI might be a new treatment option in metastatic APMN/S prostate cancer. FUNDING: Novartis.

Lu-PSMA-617 combined with ADT and ARPI reduced radiographic progression risk by 28%New Treatment Options for Men with Advanced Prostate Cancer

How this fits prior evidence

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Lu-PSMA-617 combined with ADT and ARPI reduced radiographic progression risk by 28%New Treatment Options for Men with Advanced Prostate Cancer

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