Exploration of circulating tumor cell (CTC) conversion and CTC0 as prognostic biomarkers for efficacy in TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

5023 Background: In TALAPRO-2 (NCT03395197), pts unselected for homologous recombination repair (HRR) gene alterations received TALA + ENZA or PBO + ENZA in 1L mCRPC. TALA + ENZA significantly improved radiographic progression-free survival (rPFS) vs PBO + ENZA. In a previous analysis of five randomized phase 3 mCRPC trials, CTC reduction from ≥5 to 0 to 0 (CTC0) at a Week 13 timepoint was shown to be prognostic for overall survival, with higher discriminatory power than PSA reduction (Heller et al. J Clin Oncol. 2018;36:572-580). We examined CTC conversion and CTC0 as candidate prognostic biomarkers for rPFS in TALAPRO-2. Methods: Blood was serially collected and shipped real-time for CTC enumeration using CELLSEARCH (Menarini Silicon Biosystems) at a central laboratory (Covance). Collection timepoints were screening, Weeks 1, 9, 17, and 25, and safety follow-up visit. Baseline CTC counts were based on Week 1 (screening results were used if Week 1 results were unavailable). CTC reductions were assessed in the safety population as CTC conversion or as CTC0. Data cutoff date was August 16, 2022. Results: At baseline, 653 pts in the intent-to-treat population were evaluable for CTC counts: 213/653 (33%) had CTC counts ≥5 per 7.5 mL of blood, and 353/653 (54%) had CTC counts >0. At Week 9, 144 pts were evaluable for CTC conversion (71 TALA + ENZA, 73 PBO + ENZA), with 254 evaluable for CTC0 (119 TALA + ENZA, 135 PBO + ENZA). CTC conversion at Week 9 proved prognostic for rPFS benefit for TALA + ENZA (hazard ratio HR=0.13, 95% CI 0.06–0.32, 2-sided P<0.0001) and PBO + ENZA (HR=0.16 0.07–0.40, P<0.0001). Similarly, CTC0 at Week 9 was prognostic for TALA + ENZA (HR=0.33 0.19–0.57, P<0.0001) and PBO + ENZA (HR=0.41 0.24–0.69, P=0.0006). At Week 17, 132 pts were evaluable for CTC conversion (64 TALA + ENZA, 68 PBO + ENZA), with 227 evaluable for CTC0 (114 TALA + ENZA, 113 PBO + ENZA). CTC conversion at Week 17 proved prognostic for rPFS benefit for TALA + ENZA (HR=0.28 0.10–0.73, P=0.0065) and for PBO + ENZA (HR=0.26 0.11–0.59, P=0.0006). CTC0 at Week 17 was also prognostic for TALA + ENZA (HR=0.16 0.09–0.30, P<0.0001) and for PBO + ENZA (HR=0.36 0.20–0.64, P=0.0004). Conclusions: CTC reduction at Week 9 and 17 proved prognostic of improved rPFS in both treatment arms in TALAPRO-2. To our knowledge, this is the first time such an association has been demonstrated in a phase 3 trial featuring a PARP inhibitor. Not all regions supported CTC collection, and missing results mainly reflected technical and logistical limitations. These results support the broad prognostic utility of CTC enumeration in mCRPC, particularly in the context of PARP inhibitor therapy. Clinical trial information: NCT03395197 .