Pickett, Cheryl A.

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.

PURPOSE Human epidermal growth factor receptor 2 (HER2), a transmembrane receptor with kinase activity involved in cell signaling through the RAS pathway, is expressed in osteosarcoma (OST). Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate with a HER2-targeting monoclonal antibody, trastuzumab, linked to a topoisomerase I inhibitor. We report results of a phase II study of T-DXd in adolescents and young adults with HER2-positive relapsed, unresectable OST (ClinicalTrials.gov identifier: NCT04616560 ). METHODS Patients age 12-39 years with relapsed, unresectable OST were eligible for centrally evaluated HER2 expression screening by immunohistochemistry. Patients with >10% of OST cells with cytoplasmic or membranous HER2 expression of any intensity were eligible to receive T-DXd at 5.4 mg/kg intravenously once every 3 weeks for up to 2 years. The study used a 9 + 15 Simon's optimal two-stage design with a primary end point of event-free survival at 24 weeks. RESULTS Fifty patients were screened for HER2, and 41 met the inclusion criteria of 10% of OST cells having membranous or cytoplasmic HER2 expression. Nine eligible patients, two younger than 18 years, were enrolled and received T-DXd. With a single patient having more than 24 weeks of stable disease (SD) of the nine planned in the first stage, this study did not meet criteria to progress to stage II. The estimated SD rate at 24 weeks is 11.1%. The median (range) number of cycles of therapy was 2 (2-12). Grade 3 and 4 possibly related adverse events occurred in three of nine patients and included nausea, vomiting, tumor hemorrhage, cytopenias (n = 3), wound infection, and hypertension. CONCLUSION T-DXd did not demonstrate sufficient activity to expand enrollment to the planned second stage in patients with OST. No new safety signals were observed.

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.