Testing the Combination of DS-8201a and Olaparib in HER2-Expressing Cancers With Expansion in Patients With Platinum Resistant Ovarian Cancer

PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of the combination of trastuzumab deruxtecan (DS-8201a) in combination with olaparib, and to determine the recommended phase 2 dose (RP2D). II. To evaluate the safety and tolerability of this combination in a dose expansion cohort in patients with platinum resistant high grade serous ovarian carcinoma. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity as measured by objective response rate (ORR), clinical benefit rate, progression-free survival (PFS), and duration of response (DoR). II. To measure baseline HER2 expression by immunohistochemistry (IHC) in a central laboratory and correlate with response in the dose escalation and in the dose expansion. III. To evaluate the plasma pharmacokinetic (PK) profiles of olaparib and DS-8201a metabolites when administered in combination in the dose escalation and in the dose expansion. IV. To determine markers of DNA damage response (DDR) in tumor specimens at baseline and on-treatment in patients with platinum resistant high grade serous ovarian carcinoma in dose expansion. EXPLORATORY OBJECTIVES: I. To measure baseline HER2 expression by immune multiple reaction monitoring-mass spectroscopy (ImmunoMRM), and correlate with baseline central IHC and with response in dose escalation and in dose expansion. II. To assess the formation of topoisomerase I cleaved complex formation (TOP1cc) in blood specimens and correlate with response in dose escalation and in dose expansion. III. To assess the formation of TOP1cc in paired on-treatment tumor specimens (after DS-8201a alone and after DS-8201a and olaparib combination) and correlate with response in patients with platinum resistant high grade serous ovarian carcinoma in the expansion. IV. To measure changes in HER2 expression over the course of treatment by IHC and immunoMRM and correlate with response in patients with platinum resistant high grade serous ovarian carcinoma in dose expansion. V. To determine biomarkers of response and resistance in tumor specimens and blood specimens, including whole exome sequencing (WES) and ribonucleic acid (RNA) sequencing. OUTLINE: This is a dose-escalation study of trastuzumab deruxtecan in combination with olaparib followed by a dose-expansion study. Patients receive trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1 and olaparib orally (PO) twice daily (BID) on days 1-21, days 8-14, or days 3-9 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. All patients undergo collection of blood samples, echocardiography (ECHO) or multigated acquisition scan (MUGA), computed tomography (CT), and biopsies throughout the trial. After completion of study treatment, patients are followed up for 30 days.