408P Proxalutamide plus endocrine therapy as a combination therapy in women with HR+/HER2-/AR+ metastatic breast cancer: A phase I study

This phase I clinical study aimed to assess the safety, efficacy and pharmacokinetic (PK) characteristics of proxalutamide, in combination with Endocrine therapies (ETs), in hormone-receptor (HR)+/human epidermal growth factor receptor 2 (HER2-)/AR+ metastatic breast cancer (mBC). In part 1 of the study, patients who progressed on multiple lines of therapy (≥1) were enrolled. Monotherapies were initiated including letrozole (2.5 mg/day on days 1-14) for cohort A, exemestane (25 mg/day on days 1-14) for cohort B, and fulvestrant (intramuscularly 500 mg once on days 1, 15 and 28) for cohort C, followed by proxalutamide 200 mg QD and ETs for in a 28-day cycle. In part 2 of the study, patients who either progressed on or were not tolerant to the first-line therapy were enrolled to receive proxalutamide 200 mg QD plus fulvestrant [cohort D] at a dose of 500 mg once on days 1 and 15 and day 1 of each cycle thereafter. The primary endpoint is safety and tolerability. PK and antitumor activity were also assessed. Between June 18, 2019 and Sep 5, 2022, 37 (17 in part 1 and 20 in part 2) patients received the combination therapy. No DLTs or drug-related SAEs were reported. The commonly reported Grade ≥3 TEAEs were neutrophil count decreased (3/37, 8.1%), hypokalemia (3/37, 8.1%) and bone marrow suppression (3/37, 8.1%). 6 (15.8%) patients on proxalutamide plus fulvestrant achieved a partial response and 13 (34.2%) patients had stable disease, with an overall disease control rate of 50.0% (95% CI, 33.4%–66.6%; 38.9% in part 1 and 60.0% in part 2). The overall median PFS was 6.4 months (95% CI, 2.7-19.3) for cohort C and 11.0 months (95%CI: 5.5-NA) for cohort D. PK profiles indicated rapid absorption of proxalutamide following a single dose. After multiple doses, proxalutamide and its major metabolite reached steady-state serum concentration levels at day 29 and exhibited a tendency for drug accumulation. This study suggested a good antitumor activity and safety profile of the combination therapy of proxalutamide and fulvestrant for HR+/HER2-/AR+ mBC patients in the ≥2nd-line settings. Moreover, it may provide survival benefits for these patients, warranting further investigation in a larger population.