Background: Seviteronel (sevi) is an orally bioavailable CYP17,20-lyase inhibitor that supresses androgen synthesis and inhibits androgen receptor (AR) binding and activation. In preclinical models of AR+ triple-negative breast cancer (TNBC), AR signalling promotes chemotherapy resistance through transcriptional survival programs providing a rationale for combined AR inhibition and taxane therapy. We conducted the Phase 1b open-label 4CAST trial (NCT04947189) to assess preliminary safety and preliminary efficacy of sevi in combination with taxane therapy in metastatic breast cancer (mBC), and to pilot a patient-centric decentralised enrolment and participation model aimed at reducing time toxicity and improving access. Methods: Sevi was administered at 450 mg once daily in combination with docetaxel (IV 75 mg/m2 q3wkly) or nab-paclitaxel (IV 100 mg/m2 D1/8/15 q4wkly) in patients with mBC (exploration phase) or AR+ metastatic TNBC (expansion phase). AR nuclear or cytoplasmic expression on IHC >0% assessed prospectively was required for eligibility in expansion. In the dose exploration phase, the primary objective was to assess the safety of the monotherapy recommended phase 2 dose (RP2D) of sevi plus dexamethasone in combination with taxane therapy. In the dose expansion phase, the primary objective was to assess the objective response rate (ORR) per RECIST v1.1. Secondary endpoints included frequency of adverse events (AE), duration of response, overall survival, and feasibility of decentralised participation (oral drug shipment, telehealth assessments, and local chemotherapy delivery). Exploratory analyses included serum CA15−3 and testosterone levels. Results: Dose exploration: Eight heavily pretreated patients with mBC (2 TNBC, 6 hormone receptor-positive) were enrolled with 6 evaluable for dose-limiting toxicity (DLT). No DLTs were observed, confirming the RP2D of sevi 450 mg daily. Two patients developed Grade 2 pneumonitis beyond the DLT period; one had prior sacituzumab govitecan (SG)-associated pneumonitis. Dose expansion: Eight AR+ metastatic TNBC patients were enrolled; 3 via decentralised enrolment. As of Dec 2025, 6 patients were RECIST-evaluable. The ORR was 67% (4/6), including responses in patients previously exposed to taxanes and SG. AEs were predominantly Grade 1 or 2 and attributable to taxane therapy. Sevi-related AEs were mainly Grade 1 fatigue and headache. One patient experienced grade 3 postural hypotension requiring dose reduction. Testosterone suppression was observed in all patients. Decentralised enrolment and participation were feasible for both investigators and participants. Conclusion: Sevi combined with taxane therapy was well tolerated and demonstrated encouraging antitumour activity in heavily pretreated AR+ metastatic TNBC, including patients with prior taxane exposure. These findings support AR inhibition as a strategy to overcome chemotherapy resistance and justify ongoing Phase II expansion.