Systemic and tumor-directed therapy for oligorecurrent metastatic prostate cancer (SATURN): Primary endpoint results of a phase II clinical trial.
Authors: Nikitas John , Rettig Matthew , Shen John , Reiter Robert Evan , Lee Alan , Steinberg Michael L. , Valle Luca Faustino , Sachdeva Ankush , Romero Tahmineh , Calais Jeremie , Czernin Johannes , Nickols Nicholas George , Kishan Amar Upadhyaya 
Published: January 2024

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Background: Nearly all men with metastatic hormone-sensitive prostate cancer who receive intermittent androgen deprivation therapy (ADT) will experience a relapse within six months of testosterone recovery. We hypothesized that intensifying intermittent ADT with dual next-generation androgen receptor signaling inhibitors (ARSIs) and adding metastasis-directed stereotactic body radiotherapy (SBRT) would significantly increase the number of men who remain relapse-free six months after testosterone recovery. Methods: Men with 1-5 extrapelvic metastases on prostate-specific membrane antigen (PSMA) PET/CT after initial treatment with definitive-intent radical prostatectomy were enrolled on this phase II study (NCT03902951). Men with visceral metastases were excluded. Patients were treated with 6 months of androgen annihilation therapy (AAT) using leuprolide, abiraterone acetate plus prednisone, and apalutamide. After the first month of AAT, patients received SBRT to all metastases with or without radiotherapy directed to the prostate bed and pelvic lymph nodes. The primary endpoint was the percentage of patients who maintained PSA <0.05 ng/mL six months after testosterone recovery to ≥150 ng/dL, with the study powered to detect an improvement from 1% to 12%. Secondary endpoints included progression-free survival (PFS) starting from AAT initiation and, for patients whose testosterone recovered, eugonadal PFS starting from the time of testosterone recovery. Progression was defined as PSA ≥0.05 ng/mL. Results: 28 men enrolled from March 2021-June 2022. Median follow-up was 20 months (range: 14–27 months). Twenty patients (71.4%) completed six months of ADT with dual ARSIs and SBRT, 5 patients (17.9%) completed ADT with a single ARSI and SBRT, 1 patient (3.6%) completed six months of ADT monotherapy with SBRT, and 2 patients (7.1%) withdrew prematurely. 13/26 patients (50%) maintained PSA <0.05 ng/mL six months after testosterone recovery (95% confidence interval [CI]: 32–67%) compared to the study hypothesis of 12%. Median PFS was 19.3 months (95% CI: 12.8–25.7). 1-year PFS was 69.2%. 21/26 patients (81%) had testosterone recovery at a median of 9.4 months (95% CI: 8.5–10.4) from the start of AAT. Median eugonadal PFS was 11.4 months (95% CI: 4.9–18.0). AAT had 21.4% grade 2 and 21.4% 3 toxicity rates. SBRT had 7.7% grade 2 and no grade 3 toxicity. Conclusions: Half of men with PSMA PET-defined oligorecurrent M1a-b disease who received six months of AAT and metastasis-directed SBRT remained relapse-free six months after testosterone recovery. The regimen was well tolerated, with 90% of patients completing six months of ADT and at least one next-generation ARSI. Further prospective data will evaluate whether dual ARSIs are necessary and the extent to which SBRT with short-course AAT outperforms SBRT with ADT monotherapy in this patient population. Clinical trial information: NCT03902951 .