Androgen deprivation therapy (ADT) + D is a standard-of-care for patients (pts) with de novo high-volume mHSPC, however outcomes remain sub-optimal. 177Lu-PSMA-617 (LuPSMA) has proven efficacy in metastatic castration-resistant prostate cancer, but its activity in mHSPC is unknown. We evaluated the efficacy of LuPSMA prior to D in de novo high-volume mHSPC.
Methods
We conducted an investigator-initiated, randomised, 2-arm, multi-centre, phase 2 clinical trial. Key eligibility criteria included prostate cancer diagnosed within 12 weeks of screening commencement, < 4 weeks on ADT, and high-volume (≥ 4 bone metastases with ≥ 1 outside the axial skeleton, and/or visceral metastases) PSMA-avid disease on PSMA PET/CT with no major discordance on 18FDG-PET/CT. Pts were randomized 1:1 to LuPSMA 7.5 GBq x 2 cycles followed by D (Arm A), or D alone (Arm B). All patients received ADT and D at 75mg/m2 x 6 cycles. The primary endpoint was undetectable PSA (≤ 0.2 ng/ml) at 48 weeks. Secondary endpoints included safety, freedom from castration resistance, PSA-progression-free-survival (PSA-PFS) and radiographic PFS.
Results
130 patients were randomised between April 2020 and April 2023 (Arm A: 63, Arm B: 67). 4 patients in Arm B withdrew after randomisation and 2 pts in each arm were not assessable at 48 weeks. All pts in Arm A received 2 cycles LuPSMA. 50/63 (79%) and 53/63 (84%) received 6 cycles of D in Arm A and Arm B, respectively. Undetectable PSA rates at 48 weeks were higher in Arm A vs Arm B: 41% (25/61) vs 16% (10/61), odds ratio 3.9 (95% CI 1.6-9.4), p=0.002. PSA-PFS (median 30 vs 21 months; hazard ratio (HR) 0.60 (95% CI: 0.4-1.0); p=0.039), freedom from castration-resistance (median 20 vs 16 months; HR 0.60 (95% CI: 0.4-1.0); p=0.033) and radiographic PFS (median not reached vs 22 months; HR 0.58 (95% CI: 0.3-1.0); p=0.067) were all longer in Arm A versus Arm B. Grade 3 or 4 adverse events occurred in 29% (18/63) and 27% (17/63) of patients in Arm A and Arm B respectively, typically attributable to D.
Conclusions
Sequential use of LuPSMA followed by D improved clinical outcomes in de novo high-volume mHSPC compared to D alone, without increased toxicity. Our data support a role for LuPSMA in patients with mHSPC.
Clinical trial identification
NCT04343885.