Hayes, Martin

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.

Abstract Background: DS-8201a is a HER2-targeting antibody drug conjugate with a topoisomerase 1 (top1) inhibitor payload. Preclinical evidence suggests that inhibiting PARP can potentiate top1 inhibitor-induced DNA damage and cytotoxicity. However, the clinical activity of combined top1-inhibiting chemotherapy and PARP inhibition has been limited by toxicity. We hypothesized that targeted delivery of a top1 inhibitor via DS-8201a may reduce systemic toxicity while maintaining synergistic cytotoxic activity in combination with olaparib. This combination is being investigated in the ongoing phase 1 trial CTEP #10355 (NCT04585958) in patients (pts) with advanced solid tumors expressing HER2. We present the safety analysis of pts enrolled to Module 1 (Mod 1) of dose escalation (continuous olaparib). Preliminary efficacy results are explored. Methods: Accrual was limited to pts ≥18 years old with advanced or recurrent solid tumors expressing HER2, defined as HER2 IHC ≥1+ (local testing allowed) or amplification of ERBB2 by NGS or ISH. In Mod 1, pts received DS-8201a IV once every 3 weeks and olaparib twice daily (BID) continuously in a 3+3 dose escalation design. Dose Level 1 (DL1) of Mod 1 evaluated DS-8201a dosed at 4.4mg/kg with olaparib 100mg BID Days 1-21. Dose Level 2 (DL2) of Mod 1 evaluated DS-8201a dosed at 5.4mg/kg with olaparib 100mg BID Days 1-21. The primary objective was to evaluate the safety and tolerability of combined DS-8201a + olaparib as graded by CTCAE v5. Secondary objectives include assessment of clinical activity as measured by objective response rate (ORR), clinical benefit rate (CBR; partial response [PR] + complete response [CR] + stable disease [SD] ≥6 months [mo]), median progression-free survival (PFS), and duration of response (DOR). Results: As of 30-Nov-2022, 10 pts were treated in Mod 1, with median age of 62.5 years. 10% were Asian, 10% were African American, and 80% were white. 40% had endometrial cancer and 60% had ovarian cancer. 6 of 7 pts treated on DL1 were DLT-evaluable, of which 1 patient experienced a DLT of Grade (G) 4 neutropenia. All 3 pts in DL2 were DLT-evaluable, and each experienced a DLT (2 pts with G4 febrile neutropenia, 1 pt with G4 neutropenia). Most common TRAEs in Mod 1 included: ANC decrease (60% G4, 20% G3, 20% G1/2), platelet count decrease (20% G4, 20% G3, 40% G1/2), and anemia (70% G3, 20% G1/2). All Mod 1 pts required dose holds, dose reductions, and/or discontinuation of olaparib. Of the 10 pts in Mod 1, 40% achieved a RECIST response (1 CR, 3 PR). 40% had SD lasting ≥6 mo, for a CBR of 80%. Median PFS is estimated at 7.4 mo (95% CI 4.7mo-not reached), with 7 patients alive and progression-free at 6 mo. Conclusion: Continuous dosing of olaparib in combination with DS-8201a yielded an unacceptable safety profile and dose escalation in Mod 1 was not continued. An alternative dosing schedule was initiated in Module 2 (Mod 2) evaluating DS-8201a IV every 3 weeks and olaparib BID Days 8-14; accrual to Mod 2 is ongoing. There is preliminary evidence of clinical activity of this combination. Citation Format: Elizabeth K. Lee, Andrea E. Wahner Hendrickson, Gerardo Colon-Otero, Cheryl A. Pickett, Niya Xiong, Su-Chun Cheng, Madeline Polak, Hannah Sawyer, Martin Hayes, Ursula A. Matulonis, Geoffrey I. Shapiro, Panagiotis A. Konstantinopoulos. A phase 1 study of DS-8201a in combination with olaparib in HER2-expressing malignancies (CTEP #10355): Results of module 1 dose escalation [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B041.