Lu 177 Plus Immunotherapy Displays Responses in Prostate Cancer

The addition of immunotherapy consisting of nivolumab (Opdivo) and ipilimumab (Yervoy) to lutetium-177-PSMA (Pluvicto) exhibited enhanced efficacy outcomes vs the radioligand alone as a treatment for patients with advanced castration-resistant prostate cancer (CRPC), according to a press release on findings from the phase 2 EVOLUTION trial (ANZUP2001; NCT05150236) from the Prostate Cancer Foundation of Australia.¹ Additional findings from the trial were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.²

Efficacy data revealed that the prostate-specific antigen (PSA) progression-free survival (PFS) among patients treated with the immunotherapy-based regimen was 7.6 months (95% CI, 6.5-11) vs 7.1 months (95% CI, 4.9-10) in patients treated with lutetium-177-PSMA alone for their CRPC. Additionally, the 12-month PSA-PFS rates in the arms were 33% vs 17%, respectively. The median radiographic PFS was 12 months (95% CI, 8.5-15) vs 8.5 months (95% CI, 6.0-11) in each respective arm, with 12-month rates of 47% and 23%.

“Nearly 10 years ago we discovered that targeted radiation therapy [lutetium-177-PSMA] is an effective treatment for advanced prostate cancer, slowing the spread of disease and improving the quality of life for those affected,” explained lead study author Shahneen Sandu, MBBS, FRACP, consultant medical oncologist and researcher in the Melanoma and Uro-oncology Units at the Peter MacCallum Cancer Centre in Melbourne, Australia, in the news release on the study findings.¹ “However, high numbers of people still have their disease progress while on [lutetium-177-PSMA], which means we need to keep building on existing research to find new ways of combatting treatment resistance. The [phase 2 EVOLUTION trial] allowed us to do just that, by harnessing 2 immunotherapy drugs in combination with [lutetium-177-PSMA].”

Additionally, a PSA response of 50% or greater was observed in 75% of patients treated with the radioligand plus immunotherapy vs 67% who received the radioligand alone; a PSA response of 90% of greater was observed in 46% vs 43% of each group. The objective response rate (ORR) per RECIST v1.1 criteria was 71% vs 50%. Moreover, lutetium-177-PSMA was suspended in 16% of the experimental group for deep responses.

Patients with metastatic CRPC who were previously treated with an androgen receptor pathway inhibitor (ARPI), had an ECOG performance status of 0 to 1, and had a prostate-specific membrane antigen (PSMA) maximum standardized uptake value (SUVmax) of 15 or greater at the site of disease and 10 or greater at other sites of disease were included in the phase 2 trial. Those enrolled were randomly assigned 2:1 to receive lutetium-177-PSMA at 7.5 Gbq every 6 weeks for a maximum of 6 cycles alone (n = 33) or with immunotherapy-based induction/maintenance therapy (n = 67). Induction consisted of ipilimumab at 3 mg/kg every 6 weeks for 4 cycles and nivolumab at 1 mg/kg every 3 weeks for 8 cycles; maintenance consisted of nivolumab at 480 mg every 4 weeks for a maximum of 24 months.

Those enrolled to receive the radioligand with or without immunotherapy had a median age of 71 years (IQR, 63-74) and 69 years (IQR, 64-77), respectively. The most common prior systemic treatment in each arm included docetaxel (81% vs 80%), and most patients received 1 prior ARPI (93% vs 87%). Most patients had a Gleason Score of at least 8 at diagnosis (67% vs 77%). The median PSA levels in each arm at diagnosis were 25 ng/mL (IQR, 11-73) and 20 ng/mL (IQR, 10-84).

The primary end point of the trial was the 12-month PSA-PFS rate. Secondary end points included rapid rise in PFS, adverse effects (AEs), radiographic PFS, overall survival, ORR, duration of response, and health-related quality of life.

The most common AEs in the experimental and control arms included fatigue, dry mouth, nausea, rash, anorexia, and diarrhea. The median number of lutetium-177-PSMA cycles were 5 (range, 1-6) and 6 (range, 1-6) in the experimental and control arms. In the experimental arm, the median number of ipilimumab cycles was 2 (range, 1-4), and the median number of nivolumab cycles was 3 (range, 1-24). The most common reasons for discontinuation of immunotherapy included AEs (58%), central trial decision (28%), and disease progression (13%).

References

1. World-first findings give new hope to advanced prostate cancer patients. News release. Prostate Cancer Foundation of Australia. December 22, 2025. Accessed December 23, 2025. https://tinyurl.com/5bpae79y
2. Sandhu S, Subramaniam S, Thomas H, et al. 177Lu-PSMA-617 with ipilimumab (ipi) and nivolumab (nivo) in metastatic castration-resistant prostate cancer (mCRPC): an investigator-initiated phase 2 trial (EVOLUTION; ANZUP2001). J Clin Oncol. 2025;43(suppl 16):5016. doi:10.1200/JCO.2025.43.16_suppl.5016