¹⁷⁷ Lu-PSMA-617 with ipilimumab (ipi) and nivolumab (nivo) in metastatic castration-resistant prostate cancer (mCRPC): An investigator-initiated phase 2 trial (EVOLUTION; ANZUP2001).

5016 Background: LuPSMA improves progression-free survival (PFS) and overall survival (OS) in patients with mCRPC. Immune checkpoint inhibitors (ICI) have limited single-agent activity in mCRPC. Radiation may enhance ICI activity by inducing immunogenic tumor cell death and altering the tumor microenvironment. We evaluated the activity and safety of ipi plus nivo plus LuPSMA in mCRPC. Methods: Eligibility: prior androgen receptor pathway inhibitor therapy, PSMA-positive disease, normal organ function, no contraindications to ICIs, <= 1 line of chemotherapy. Randomized (1:2) to LuPSMA alone (7.4 GBq every 6 weeks, up to 6 doses) or LuPSMA plus induction ipi (3 mg/kg every 6 weeks for 4 doses) and nivo (1 mg/kg every 3 weeks for 8 doses) followed by maintenance nivo (480 mg every 4 weeks for 18 doses) (LuPSMA+ICI). Primary endpoint: PSA PFS at 12 months (PSA-PFS 12m). Secondary endpoints: PSA response rate (PSA-RR), adverse events (AEs), radiographic-PFS (rPFS), PSA-PFS, and OS. Results: 93 of 100 planned participants (pts) were randomized from July 2022 to July 2023. Recruitment was stopped early due to 4 cases of treatment-related myocarditis in pts assigned LuPSMA+ICI. Of 93 randomized, 30 pts received LuPSMA, 57 pts received LuPSMA+ICI. 6 pts who did not receive assigned LuPSMA+ICI (1 ineligible; 5 ceased ICI at the direction of the central study team) were excluded from the efficacy intention to treat analysis. However, 5 were included in the safety analysis. Median age was 70 years [range: 45-83]; 80% had prior docetaxel. The median follow-up was 18 months (IQR: 16-22). PSA-PFS 12m was higher in pts assigned LuPSMA+ICI than LuPSMA-alone (33% vs. 17%, see table). Grade 3-4 AEs were reported in more pts assigned LuPSMA+ICI than LuPSMA-alone (75% vs 29%). Among those assigned LuPSMA+ICI, Grade 3-4 AEs 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 pts (7%) assigned LuPSMA+ICI. There were 2 deaths during LuPSMA+ICI treatment: myocarditis (treatment related) and sepsis (not treatment related). Conclusions: LuPSMA+ICI was associated with improved PSA-PFS 12m in mCRPC. The spectrum of AEs were keeping with established toxicities however significantly higher with LuPSMA+ICI, and frequency of ICI-related myocarditis lead to early trial cessation. Clinical trial information: NCT05150236 . LuPSMA+ICI (N=57) LuPSMA alone (N=30) Median (IQR) LuPSMA cycles 5 (4-6) 6 (4-6) Median (IQR) cycles of ipi 2 (1-3) Median (IQR) cycles of nivo 3 (2-5) PSA-PFS 12m, % 33 17 PSA-PFS, median, months 7.6 (95% CI: 6.5, 11) 7.1 (95% CI: 4.9, 10) HR (95% CI) 0.70 (0.43, 1.13) PSA 50% (95% CI) 75% (62, 85) 67% (47, 82) PSA 90% (95% CI) 46% (33, 59) 43% (26, 62) Pts with grade 3-4 AEs 43/57* (75%) 10/35* (29%) *Safety population.