Systemic and Tumor-Directed Therapy for Oligorecurrent Metastatic Prostate Cancer (SATURN): Primary Endpoint Results of a Phase II Clinical Trial

Purpose: Nearly all men with metastatic hormone-sensitive prostate cancer who receive intermittent androgen deprivation therapy (ADT) will experience disease recurrence 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 recurrence-free six months after testosterone recovery.

Methodology: This phase II clinical trial (NCT03902951) enrolled men with 1-5 non-visceral, extrapelvic metastases on prostate-specific membrane antigen (PSMA) PET/CT after initial treatment with definitive-intent radical prostatectomy. Intra-pelvic nodal metastases (N1 disease) of any number were allowed. Patients were treated with six 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: Twenty-eight 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, five patients (17.9%) completed ADT with a single ARSI and SBRT, one patient (3.6%) completed six months of ADT monotherapy with SBRT, and two patients (7.1%) withdrew prematurely. Thirteen patients (50%) maintained a 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). The one-year PFS rate was 69.2% (95% CI: 51.4-87.0%). 22/26 patients (85%) had testosterone recovery at time of last follow-up. Median time to testosterone recovery was 9.8 months (95% CI: 7.5–12.2) from the start of AAT. Median eugonadal PFS was 11.4 months (95% CI: 4.8–18.0). The one-year eugonadal PFS rate was 31.1% (95% CI: 0.5-61.7%). AAT had 21.4% grade 2 and 21.4% grade 3 toxicity rates. SBRT had 7.7% grade 2 and 0% grade 3 toxicity rates.

Conclusions: Half of men with PSMA PET-defined oligorecurrent M1a-b disease who received six months of AAT and metastasis-directed SBRT remained recurrence-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.

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