Study explores toxicity reduction in combination of trastuzumab deruxtecan and olaparib in HER2-expressing malignancies

A phase 1 study aiming to test tolerability of combination therapy with trastuzumab deruxtecan and olaparib in Human Epidermal Growth Factor Receptor 2 (HER2)-expressing malignancies—including ovarian and uterine cancers—found a tolerable dosing schedule with promising activity, according to results reported by Dana-Farber Cancer Institute medical oncologist Dr. Elizabeth Lee at the AACR Annual Meeting 2026, held April 17–22, in San Diego, Calif.

Previous preclinical studies suggest that PARP inhibitors and topoisomerase 1 (topo1) inhibitors work well together. This synergy, however, has been limited by toxicity and poor efficacy in previous clinical trials that used topo1 inhibiting chemotherapy. Lee and colleagues hypothesized that targeted delivery of a topo1 inhibitor via an antibody drug conjugate could improve both toxicity and anti-tumor efficacy.

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that targets and binds tumor cells overexpressing HER2. This antibody conjugate carries a topo1 inhibitor, a potent DNA-damaging agent, adding precision that reduces death of neighboring healthy cells. Olaparib is a PARP inhibitor that blocks cancer cells from repairing their DNA, causing them to die.

This study, CTEP #10355, was initiated by Dana-Farber investigators to explore approaches to dosing with an aim to home in on a regimen that maintains efficacy and improves tolerability.

“The goal is to kill more cancer cells effectively while minimizing damage to healthy cells,” said Lee, who is principal investigator of the study.

The phase 1 trial evaluated 28 participants with HER2-expressing advanced and recurrent solid tumors, including 16 patients with ovarian cancer and 12 with uterine cancer. Participants were given T-DXd, which is also called DS-8201a, once every three weeks while gradually increasing the dosage. Olaparib dosing was on continuous and intermittent schedules.

Patients were enrolled across three groups that studied the combination in varying doses and schedules with the intent to maximize the synergistic effect of the combination and minimize adverse effects. Patients in module 1 received continuous treatment with olaparib with a lower initial dosing of T-DXd. Patients in module 2 received intermittent treatment with olaparib on days 8 through 14 with a standard higher dose of T-DXd. Patients in module 3 received intermittent treatment with olaparib days 3 through 9 with a standard higher dose of T-DXd.

Patients in module 1 and module 3 experienced dose-limiting toxicities, related to low blood counts. Enrollment in these groups was halted.

Module 2 treatment schedule and maximum tested dose was found to be tolerable for patients, with only one person experiencing dose-limiting colitis, which is a known side effect of T-DXd. Patients still experienced grade 3 and grade 4 low blood counts, but much less frequently compared to module 1. For instance, 12% of patients in module 2 experienced grade 3 neutropenia compared with 30% in module 1. Similarly, 25% in module 2 experienced grade 3 anemia versus 70% in module 1.

Anti-cancer activity of combined T-DXd and olaparib was seen across dosing schedule modules, tumor types and levels of HER2 expression, with an objective response rate (ORR) of 54% and a confirmed ORR of 46%. The responses include a patient with a confirmed complete response and 12 patients with confirmed partial responses. Additionally, 19 patients were alive and progression-free at six months, and the median progression-free survival was 15.2 months.

The module 2 treatment regimen was selected as the dose that will be evaluated in additional patients in a dose expansion study.

“Therapies that reduce systemic toxicity in patients with HER2-expressing advanced solid tumors is a major unmet need, and this trial is a significant step in the broader effort to expand treatment options for this population,” Lee said.