PROTRACT: A randomized phase II trial comparing ctDNA-guided biomarker directed therapy vs patient/clinician’s choice for metastatic castration resistant prostate cancer (mCRPC) progressing after abiraterone plus prednisone (AAP).

Abstract

5017 Background: A subset of mCRPC patients (pts) will benefit from enzalutamide (ENZA) following disease progression on AAP. Preliminary data suggests that higher plasma ctDNA/total cfDNA fraction (ctDNA%) post-AAP predicts poor response to ENZA but preserved sensitivity to docetaxel (DOC). We hypothesize that ctDNA%-guided selection of enzalutamide or docetaxel in chemotherapy-naïve mCRPC post-abiraterone will improve clinical outcomes versus patient/clinician’s choice of treatment. Methods: A multi-centre, open-label, phase II trial randomized mCRPC pts progressing after AAP 1:1 to biomarker-directed therapy (Arm A: ctDNA% ≥2% receives DOC; ctDNA% <2% receives ENZA) or clinician’s choice of ENZA or DOC (Arm B, ctDNA% blinded). Baseline ctDNA% was assessed at screening using somatic mutations and genome-wide ploidy models. At progression, eligible pts could cross over to the alternative therapy. The primary endpoint was progression-free survival (PFS) defined as the time from treatment initiation to first documented disease progression (clinical, radiological, or PSA) or death from any cause. PFS was estimated using the Kaplan-Meier method and compared between arms using the log-rank tests. Secondary endpoints included PSA50 response (PSA decline ≥50% from baseline) and overall survival (OS). Results: Between October 2020 and June 2025, 56 pts were screened and 42 randomized 1:1 to Arm A (n=17) or Arm B (n=25). The trial was terminated due to slow accrual prior to the planned enrollment of 100 patients. At data cut-off (January 7, 2026), median follow-up was 38.0 months, and 94% (Arm A) and 92% (Arm B) had experienced disease progression or death. Baseline characteristics were balanced. ctDNA% <2% was observed in 35.3% and 32% of pts in Arm A and B, respectively. In Arm A, 11 pts were assigned to and received DOC (ctDNA% ≥2%) and 6 pts to ENZA (ctDNA <2%). In Arm B patient/clinician choice was DOC in 4 patients (3 pts with ctDNA ≥2%) and ENZA in 21 patients (7 pts with ctDNA <2%). PFS, OS and PSA50 all favoured biomarker directed therapy (Arm A) (Table). Conclusions: In this clinical utility study, ctDNA% to guide ENZA or DOC selection in patients previously treated with AAP led to superior PFS and OS compared to patient/clinician-selected therapy. These hypothesis-generating results illustrate the potential for ctDNA% as a predictive biomarker to assist in clinical decision making and support further studies. Clinical trial information: NCT04015622 . Primary & secondary outcomes. Biomarker-Directed (Arm A, n=17) Clinician’s Choice (Arm B, n=25) HR (95% CI) P-Value Progression-Free Survival (PFS), Months, median (95% CI) 5.6 (3.2-8.2) 2.5 (1.5-3.7) 0.4 (0.2-0.8) p = 0.01 PSA50 Response (%) 52.9% 28.0% p = 0.12 Overall Survival (OS), months, median (95% CI) 46.3 (12.2-NR) 15.3 (13.5-20.7) 0.4 (0.2-0.9) p = 0.04