Abstract Background: ACE-106 (ACE-86225106) is a highly selective PARP1 inhibitor designed to improve the therapeutic index relative to first-generation pan-PARP inhibitors. Here, we report the updated data from the first-in-human study (NCT06380660). Method: The study comprises a “3+3” dose escalation module and a backfill module. Patients (pts) with advanced or metastatic solid tumors were treated with ACE-106 monotherapy QD PO. Enrollment in the backfill module required germline or somatic HRR mutations (HRRm), including BRCA1/2, PALB2, or CDK12 mutations, while the dose escalation module allowed pts without HRRm. The primary objective was safety; secondary objectives were PK, pharmacodynamics, and preliminary efficacy. Result: As data cut-off (Dec 31, 2025), 52 pts received ACE-106 at dose levels ranging from 5-80 mg, with a median treatment duration of 2. 1 (range 0. 6-18. 4) months. The pts had a median 4 (range 1-12) lines of prior systemic therapy, and 29% had prior PARPi. ACE-106 was well tolerated across all dose levels, with no dose-limiting toxicities or grade 4-5 treatment-related adverse events (TRAEs). No TRAEs leading to dose reduction or discontinuation were reported. Grade 3 TRAEs occurred in 17% of pts, with the most common being anemia (10%), decreased platelet count (2%), decreased lymphocyte count (2%), decreased appetite (2%), and vomiting (2%). Hematological toxicity did not increase along with the dose level. Among 16 pts with HRRm evaluable for radiological response per RECIST1. 1 criteria, objective response rate (ORR) was 38% (6/16) with the longest duration of response of 12 months; and disease control rate (DCR) was 75% (12/16). Notably, among metastatic castration-resistant prostate cancer (mCRPC) pts with HRRm, ORR was 50% (4/8) and PSA50 response rate was 42% (5/12). One mCRPC pt without HRRm also had a confirmed partial response. Among advanced ovarian cancer (OC) pts who were naïve to pan-PARPi, ORR was 67% (2/3) and DCR was 100%. ACE-106 demonstrated a flat PK curve (Cmax was 1. 4-2. 3 fold of Cmin) across all 6 doses, with a mean T1/2 of 20. 6-34. 5 hours supporting QD dosing. Drug exposure increased proportionally with dose, and up to 69 fold of Cmin to target effective concentration (TEC) ratio was observed at 80mg QD. Conclusion: ACE-106 was well tolerated and showed promising efficacy and excellent PK properties in heavily pre-treated advanced solid tumors. The clinical profile suggests a best-in-class selective PARP1i potential to replace pan-PARPi and justify further development of ACE-106-based combination therapy. Disclosure: This abstract used generative AI to help revise content written by authors. Citation Format: Xingyun Cai, Jian Zhang, Yu Chen, Yanxia Shi, Wei Wang, Zhanhong Chen, Jiongjie Chen. Updated results from a first-in-human phase 1, 2 study of ACE-106, a highly selective and potentially best-in-class PARP1 inhibitor in advanced solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT064.
Cai et al. (Fri,) studied this question.