Purpose <p>DHP107 is an oral paclitaxel enabling administration of paclitaxel without Cremophor EL, a vehicle used to improve the solubility of intravenous (IV) paclitaxel. The randomized phase II OPERA study investigated the efficacy and safety of DHP107 versus IV paclitaxel in patients with HER2-negative breast cancer.</p> Methods <p>OPERA was conducted in the USA and Czech Republic. Patients were ≥ 18&#xa0;years, with measurable disease, and histologically or cytologically confirmed recurrent or metastatic breast cancer with any tumor hormone receptor status. Patients were randomized 2:1 to DHP107 (200&#xa0;mg/m² po bid with premedication if needed on days 1, 8, and 15, every 28&#xa0;days) or IV paclitaxel (80&#xa0;mg/m² with standard premedication on days 1, 8, and 15 every 28&#xa0;days). The primary objective was DHP107 efficacy; secondary objectives included DHP107 safety and tolerability.</p> Results <p>72 patients were randomized, 48 to DHP107 and 24 to IV paclitaxel. There was one complete response and 11 partial responses with DHP107 (objective response rate [ORR 25.0%; 90% CI 15.1–37.3), and six partial responses with IV paclitaxel (objective response rate [ORR] 28.6%; 90% CI 13.2–48.7; <i>p</i> = 0.7559). Median progression-free survival (PFS) was 5.5&#xa0;months for DHP107 and 4.7&#xa0;months for IV paclitaxel (<i>p</i> = 0.8018); median overall survival (OS) was 17.1 and 13.2&#xa0;months, respectively (<i>p</i> = 0.7629). Common all-grade adverse events were diarrhea (68.8%), nausea (64.6%), and fatigue (52.1%) for DHP107 and fatigue (47.6%), peripheral neuropathy (42.9%), and alopecia (42.9%) for IV paclitaxel.</p> Conclusion <p>DHP107 is a tolerable and feasible treatment for patients with recurrent or metastatic HER2-negative breast cancer, with similar efficacy and safety to IV paclitaxel.</p> <p><b>Clinicaltrials.gov no:</b> NCT03326102; date of registration October 19, 2017.</p>