A phase 2 trial of darolutamide to enhance prostate-specific membrane antigen expression in patients with localized prostate cancer (Daro-PET).

310 Background: PSMA PET/CT improves prostate cancer detection and guides PSMA-targeted therapies. Preclinical data suggest androgen receptor pathway inhibitors (ARPIs) may transiently upregulate PSMA expression in the metastatic setting, but prospective evidence in localized disease is lacking. Methods: Daro-PET (NCT05900973) was a single-arm, Simon’s two-stage phase 2 trial of men ≥18 years with localized prostate adenocarcinoma, no metastasis on CT/MRI or bone scan, and scheduled for prostatectomy. Patients had a baseline PSMA PET/CT, received darolutamide 600 mg twice daily for 7 days, then a second PSMA PET/CT. The primary endpoint was the proportion with ≥20% SUVmax increase in the intention-to-treat (ITT) set. Secondary endpoints were changes in tumor volume, SUVmean, total lesion PSMA, new metastases, and safety, plus per-protocol analyses (radiotracer dose 4.0 ± 1.0 mCi, ≤30% variation). Sample size assumed 80% power, one-sided α=0.05. If ≥3 patients met the primary endpoint, the regimen would be considered worthy of further study. Results: Between July 2023 and March 2025, 16 patients were enrolled (median age 61 IQR 55–70; 50% ISUP grade 4; 62.5% cT3; median PSA 10 ng/mL IQR 6.4–11.2). Baseline PSMA PET/CT showed nodal involvement in 4 patients and multifocal prostate uptake in 4 patients. No adverse events were reported, and all patients completed treatment. In ITT, 3 of 16 patients (18.8%; 90% CI 5.3–41.7) met the primary endpoint, with SUVmax increases of 36.5–62%. In per-protocol, 3 of 14 (21.4%; 90% confidence interval CI 6.1–46.6) achieved ≥20% SUVmax rise. Seven of 14 patients (50%; 90% CI 26.4–73.6) showed increased tumor volume (ranging from 6.2% to 98.6%). SUVmean and total lesion PSMA increased in 3 patients (21.4%). No new pelvic or extrapelvic metastases were detected. Two patients did not undergo prostatectomy due to shared decision-making unrelated to PET findings. Conclusions: A 7-day course of darolutamide increased PSMA expression in a subset of men with high-risk localized prostate cancer. These findings support further evaluation of ARPIs to improve the performance of PSMA PET/CT and PSMA-targeted therapies. Funding: Instituto D’Or de Pesquisa e Ensino, Bayer, RPH. Clinical trial information: NCT05900973 .