Abstract CT035: CTEP #10355 A phase 1 trial of DS-8201a and olaparib in HER2-expressing malignancies: Results from dose escalation

Abstract Background: DS-8201a is a HER2-targeting antibody drug conjugate with a topoisomerase 1 (topo1) inhibitor payload. Preclinical evidence suggests that inhibiting PARP can potentiate topo1 inhibitor-induced DNA damage and cytotoxicity. However, the clinical activity of combined topo1-inhibiting chemotherapy and PARP inhibition has been limited by toxicity. We hypothesized that targeted delivery of a topo1 inhibitor via DS-8201a may reduce systemic toxicity, while maintaining synergistic cytotoxic activity in combination with olaparib (PARPi). DS-8201a + olaparib was evaluated in the ongoing CTEP #10355 trial (NCT04585958). Results from Dose Escalation are presented. Methods: Accrual was limited to pts ≥18 years old with advanced or recurrent solid tumors expressing HER2, defined as HER2 IHC ≥1+ or ERBB2 amplification by NGS or ISH (local testing allowed). DS-8201a was given Q3W across all dose escalation regimens. Olaparib dosing in continuous (Module 1 D1-21) and intermittent schedules (Module 2 D8-14; Module 3 D3-9) were explored. A 3+3 dose escalation design was followed in Mod 1 & 2 and up to 6 pts in a safety cohort were planned for Mod 3. Primary endpoints included safety as graded by CTCAE v5 and determination of an RP2D. Results: As of Oct 26, 2025, 30 pts were enrolled and 28 pts were treated. 12 pts had uterine and 16 pts had ovarian cancer; mean age was 61.6 years, median number of prior therapies was 4 (range 1-10). HER2 expression by local testing was: 4 pts IHC 1+, 17 pts IHC 2+, 6 pts IHC 3+, 1 pt ERBB2 amplification (IHC not reported). 9/10 pts enrolled in Mod 1 (continuous olaparib) were DLT-evaluable: 1/7 pts at DL1 (DS-8201a 4.4mg/kg IV Q3W + olaparib 100mg BID D1-21) and 3/3 pts at DL2 (DS-8201a 5.4mg/kg IV Q3W + olaparib 100mg BID D1-21) experienced DLTs (G4 neutropenia, febrile neutropenia, WBC decrease, colitis), halting further Mod 1 enrollment. 12/16 pts enrolled to Mod 2 (intermittent olaparib) were DLT-evaluable and only 1 pt at the highest dose level (DL3, DS-8201a 5.4mg/kg IV Q3W + olaparib 300mg BID D8-14) experienced a DLT (G3 colitis). Hematologic TRAEs were markedly attenuated in Mod 2 compared to Mod 1: 12% vs 30% G3 and 19% vs 50% G4 neutropenia; 25% vs 70% G3 anemia; 6% vs 20% G3 and 0% vs 20% G4 thrombocytopenia. 2/2 DLT-evaluable pts in Mod 3 (intermittent olaparib; DS-8201a 5.4mg/kg IV Q3W + olaparib 300mg BID D3-9) experienced DLTs (G3 diarrhea, G3 nausea & vomiting, G4 neutropenia), halting further Mod 3 enrollment. The Mod 2 DL3 regimen of DS-8201a 5.4mg/kg IV Q3W + olaparib 300mg BID D8-14 was declared the RP2D and is under further investigation in an ongoing Dose Expansion cohort enrolling HER2 IHC 1+ platinum resistant ovarian cancer. Objective responses were observed across all modules and dose levels. Conclusions: In pts with HER2-expressing advanced solid tumors, DS-8201a in combination with intermittently-dosed olaparib was tolerable. DS-8201a 5.4mg/kg IV Q3W + olaparib 300mg BID D8-14 was selected as the RP2D for further evaluation in Dose Expansion. Additional endpoints of clinical activity will be presented. Citation Format: Elizabeth K. Lee, Andrea Wahner Hendrickson, Gerardo Colon-Otero, Cheryl A. Pickett, Yinglu Zhou, Su-Chun Cheng, Madeline Polak, Hannah Sawyer, Martin Hayes, Ursula A. Matulonis, Geoffrey I. Shapiro, Panagiotis A. Konstantinopoulos. CTEP #10355 A phase 1 trial of DS-8201a and olaparib in HER2-expressing malignancies: Results from dose escalation [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(8_Suppl):Abstract nr CT035.