When Dr. Elizabeth Lee and her team at Dana-Farber Cancer Institute set out to tackle a stubborn problem in cancer treatment — how to combine two powerful drugs without overwhelming side effects — they began with a simple but ambitious goal: kill more cancer cells while causing less harm to healthy ones. The results, presented at the AACR Annual Meeting 2026 in San Diego, suggest they may have found a path forward.
The phase 1 trial enrolled 28 patients with HER2-expressing ovarian and uterine cancers — 16 and 12 participants respectively — and tested a novel pairing: trastuzumab deruxtecan, an antibody-drug conjugate that delivers a potent DNA-damaging agent directly to tumor cells, with olaparib, a PARP inhibitor that prevents cancer cells from repairing their own DNA. Previous attempts to combine PARP inhibitors with topoisomerase 1 inhibitors had shown promise in laboratory studies but ran into a wall of toxicity in clinical trials.
The researchers organized participants into three groups testing different dosing schedules. Two groups — module 1 and module 3 — experienced dose-limiting toxicities related to low blood counts, and enrollment in those arms was halted. But module 2, which used intermittent olaparib dosing from days 8 through 14 alongside a standard dose of trastuzumab deruxtecan, proved tolerable. Only one patient experienced dose-limiting colitis, a known side effect of the antibody conjugate.
The difference in side effect severity was striking. In module 2, just 12 percent of patients developed grade 3 neutropenia, compared with 30 percent in module 1. Grade 3 anemia occurred in 25 percent of module 2 patients, down dramatically from 70 percent in module 1. These reductions matter: fewer severe blood count drops mean patients can stay on treatment longer and feel better doing so.
Beyond tolerability, the combination showed meaningful anti-cancer activity. The objective response rate reached 54 percent, with a confirmed response rate of 46 percent — including one complete response and twelve partial responses. Nineteen patients remained alive and progression-free at six months, and the median progression-free survival stretched to 15.2 months.
"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. The module 2 regimen has been selected for further study in an expansion cohort, bringing researchers closer to answers that could reshape treatment for thousands of patients facing limited options today.