(UroToday.com) The 2025 ASCO annual meeting featured a prostate cancer rapid oral abstract session and a presentation by Dr. Shahneen Sandhu discussing the results from EVOLUTION, an investigator initiated phase 2 trial assessing 177Lu-PSMA-617 with ipilimumab and nivolumab in metastatic castration-resistant prostate cancer (mCRPC). 177Lu-PSMA-617 improves progression free survival and overall survival in patients with mCRPC, however, immune checkpoint inhibitors have limited single-agent activity in this disease space. Importantly, radiation may enhance immune checkpoint inhibitors activity by inducing immunogenic tumor cell death and altering the tumor microenvironment. At the 2025 ASCO annual meeting, Dr. Sandhu evaluated the activity and safety of ipilimumab + nivolumab + 177Lu-PSMA-617 in mCRPC.
For this phase 2 trial, eligibility included: prior androgen receptor pathway inhibitor therapy, PSMA-positive disease, normal organ function, no contraindications to immune checkpoint inhibitors, and <= 1 line of chemotherapy. Patients were randomized (1:2) to 177Lu-PSMA-617 alone (7.4 GBq every 6 weeks, up to 6 doses) or 177Lu-PSMA-617 + induction ipilimumab (3 mg/kg every 6 weeks for 4 doses) and nivolumab (1 mg/kg every 3 weeks for 8 doses) followed by maintenance nivolumab (480 mg every 4 weeks for 18 doses) (177Lu-PSMA-617 + immune checkpoint inhibitor). The trial design of EVOLUTION is as follows:
The primary endpoint was PSA progression free survival at 12 months (PSA progression free survival 12 months), and secondary endpoints included PSA response rate, adverse events, radiographic progression free survival, PSA progression free survival, and overall survival.
Overall, 93 of 100 planned participants were randomized from July 2022 to July 2023. Recruitment was stopped early due to 4 cases of treatment-related myocarditis in participants assigned 177Lu-PSMA-617 + immune checkpoint inhibitor. The trial management committee determined that 11 patients having ongoing nivolumab + ipilimumab induction be stopped, four patients having ongoing nivolumab maintenance be stopped, and participants randomized to nivolumab + ipilimumab who had not commenced treatment were offered 177Lu-PSMA-617 alone (n = 6, not included in these analyses, 5 were included in the safe analysis). Of 93 randomized, 30 participants received 177Lu-PSMA-617, and 57 participants received 177Lu-PSMA-617 + immune checkpoint inhibitor.
The median age was 70 years [range: 45-83], and 80% had prior docetaxel:
Over a median follow-up of 18 months (IQR: 16-22), PSA progression free survival at 12 months was higher in participants assigned 177Lu-PSMA-617 + immune checkpoint inhibitors than 177Lu-PSMA-617-alone (33% versus 17%; HR 0.71, 95% CI 0.43-1.19), in addition to improvement in radiographic progression free survival (47% versus 23%; HR 0.53, 95% CI 0.32-0.90):
177Lu-PSMA-617 + immune checkpoint inhibitors also resulted in numerically better PSA responses, and an improvement in objective response rate (71% versus 50%) compared to 177Lu-PSMA-617 alone:
Grade 3-4 adverse events were reported in more participants assigned 177Lu-PSMA-617 + immune checkpoint inhibitors than 177Lu-PSMA-617-alone (75% versus 29%). Among those assigned 177Lu-PSMA-617 + immune checkpoint inhibitors, Grade 3-4 adverse events in ≤5% were: colitis (19%), anemia (11%), hypophysitis (14%), lung infection (9%), fatigue (7%), thrombocytopenia (7%), hepatitis (7%), pneumonitis (7%), thromboembolic event (5%), and rash (5%). Myocarditis was reported in 4 participants (7%) assigned 177Lu-PSMA-617 + immune checkpoint inhibitors. There were 2 deaths during 177Lu-PSMA-617 + immune checkpoint inhibitor treatment: myocarditis (treatment related) and sepsis (not treatment related):
Dr. Sandhu concluded her presentation discussing the results from EVOLUTION with the following take home points:
- This was a first-in-field, investigator initiated phase 2 trial of 177Lu-PSMA-617 +/- ipilimumab and nivolumab, with the results warranting further research:
- PSA progression free survival at 12 months: 33% versus 17%
- Median radiographic progression free survival: 12 months versus 8.5 months
- PSA50: 75% versus 67%
- Grade 3-4 adverse events: 76% versus 29%
- Toxicities were consistent with 177Lu-PSMA-617 and immune checkpoint inhibitors
- Genomic, immunologic, and imaging biomarker analyses are ongoing to:
- Understand effects of 177Lu-PSMA-617 and immunotherapy on the tumor microenvironment
- Optimize patient selection
Presented by: Shahneen Sandhu, Peter MacCallum Cancer Center and the University of Melbourne, Melbourne, Australia
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting, Chicago, IL, Fri, May 30 – Tues, Jun 3, 2025.