Circulating Tumor DNA in Oligoprogressive Prostate Cancer Treated With Stereotactic Radiotherapy: A Prespecified Secondary Analysis of a Nonrandomized Clinical Trial

Importance Stereotactic body radiotherapy (SBRT) is increasingly used for oligoprogressive prostate cancer, but the duration of disease control is highly variable. Objective To evaluate time to progression based on circulating tumor DNA (ctDNA) prior to SBRT. Design, Setting, and Participants Between October 17, 2018, and February 1, 2023, the phase 2 prospective, single-arm, nonrandomized clinical TRAP (Targeted Radiotherapy in Androgen-Suppressed Prostate Cancer Patients) trial evaluated SBRT to treat 81 patients with castration-resistant prostate cancer (CRPC) and 2 or fewer metastases and imaging evidence of progression while receiving an androgen receptor pathway inhibitor (ARPI). Plasma DNA was collected at 1 or 2 points prior to SBRT and centrally tested for ctDNA using the next-generation sequencing assay PCF_SELECT. Data were collected prospectively using electronic trial case report forms. Data were extracted November 26, 2025. The median follow-up was 24.5 (IQR, 23.7-36.3) months. Exposures Progressing metastases were treated with SBRT, and patients were followed up with clinical assessments, serum prostate-specific antigen (PSA) tests, and imaging. Main Outcomes and Measures The primary outcome measure was time to progression, defined as an increase in serum prostate-specific antigen level of 25% or greater from the post-SBRT nadir, radiologic or symptomatic progression, clinician decision to stop ARPI, or death from any cause. The secondary outcomes were time to next therapy or death from any cause. All end points were measured from time of final SBRT treatment. Results Of 77 patients with evaluable blood samples taken prior to SBRT, 19 (24.7%) were in the ctDNA-positive group. The 6-month progression-free survival (PFS) rate was 21.1% (95% CI, 6.6%-41.0%) for the ctDNA-positive group compared with 58.3% (95% CI, 44.5%-69.8%) for the ctDNA-negative group. The median PFS was 3.0 (95% CI, 2.7-5.9) months for the ctDNA-positive group and 7.8 (95% CI, 5.9-11.4) months for the ctDNA negative group (log rank test, P = .003 at 5% significance level). The median time to initiation of a new therapy or death was 15.3 (95% CI, 4.7-26.0) months for the ctDNA-positive group and 29.6 (95% CI, 17.8-37.6) months for the ctDNA-negative group. The median overall survival was 27.2 (95% CI, 19.2 to undefined) months for the ctDNA-positive group and 33.6 (95% CI, 28.4-38.2) months for the ctDNA-negative group. Conclusions and Relevance These findings suggest that for patients with oligoprogression and no ctDNA, SBRT and continued ARPI could be considered a valid option for prolonging disease control. Trial Registration ClinicalTrials.gov Identifier: NCT03644303