¹⁷⁷ Lu-PSMA-617 consolidation therapy post docetaxel in patients with de-novo high-volume metastatic hormone-sensitive prostate cancer: A randomized, phase 2 trial.

5095 Background: De-novo high-volume metastatic hormone-sensitive prostate cancer (mHSPC) presents a therapeutic challenge with a dismal five-year survival rate. Till recently, androgen deprivation therapy (ADT) with docetaxel had been the standard-of-care for such patients. Nevertheless, a substantial proportion of patients continue to harbour residual disease after completion of docetaxel. 177 Lu-PSMA-617 has shown positive survival outcomes in the metastatic castrate-resistant setting. Here, we intended to evaluate the role of upfront 177 Lu-PSMA-617 as consolidation therapy for residual disease following docetaxel in de-novo high-volume mHSPC patients. Methods: This was an investigator-initiated randomized, parallel-group, open-label, phase 2 trial. Patients with de-novo high-volume mHSPC who were initiated on ADT plus docetaxel (75 mg/m 2 /cycle x 6) and had residual non-progressive disease after completion of six cycles of docetaxel (defined as serum PSA >0.2 ng/mL with PSMA-positive disease on 68 Ga-PSMA-11 PET/CT) were randomized in 1:1 ratio to the experimental arm ( 177 Lu-PSMA-617, 7.4 GBq/cycle x 2, 6 weeks apart with continued ADT) or control arm (continued ADT only). The primary end-point was the proportion of patients achieving a serum PSA of ≤0.2 ng/mL at 6 months from randomization. Major secondary end-points included radiographic progression-free survival (rPFS), PSA-PFS, and treatment-emergent adverse events (TEAEs). A total sample size of 78 patients was estimated to be recruited assuming a 30% improvement in the primary end-point in the experimental arm with two-sided alpha of 5% and power of 80%. Results: The trial was terminated early due to poor accrual COVID-19 pandemic and following the change in standard of care from doublet to triplet therapy incorporating an androgen-receptor pathway inhibitor along with ADT plus docetaxel. Thirty high-volume mHSPC patients (15 in each arm) were recruited between January 2021 and May 2024. The primary end-point was achieved in 9/15 (60%) patients in the experimental arm versus 2/15 (13.3%) patients in the control arm (risk ratio: 4.5, 95% CI: 1.2-17.4, p=0.008). The median rPFS was 18 months in the experimental arm versus 9 months in the control arm, while the median PSA-PFS were 15 months and 9 months, respectively. No major grade 3/4 TEAEs were seen in the experimental arm. Conclusions: In de-novo high-volume mHSPC patients treated with docetaxel and having residual disease, 177 Lu-PSMA-617 consolidation therapy demonstrated remarkable efficacy in terms of biochemical response. Larger phase 3 trials are needed to definitively establish its survival benefits. Clinical trial information: CTRI/2021/01/030267 .