Background: Alterations activating the PI3K-AKT pathway are found in 40-50% of patients with aggressive prostate cancer. This leads to an abrogated response to therapy with androgen-receptor (AR) pathway inhibitors (ARPIs) and is associated with poor outcomes. Preclinical in vivo models suggest there is synergy between ARPIs and AKT inhibitors. Methods: This is a single-arm study of the AR inhibitor darolutamide, the AKT inhibitor ipatasertib, and androgen deprivation therapy (ADT). The phase I safety cohort included patients with castration-resistant prostate cancer (CRPC). ADT was administered per institutional standards. Patients started with a lead-in of ipatasertib for 7 days, followed by ipatasertib combined with darolutamide 600 mg BID. The starting dose of ipatasertib was 400 mg daily with plans to de-escalate if ≥ 2 dose-limiting toxicities (DLTs) were identified in the first six patients. The DLT period was the first 4 weeks of combination therapy. The primary endpoint was to identify the recommended phase II dose (RP2D) of ipatasertib. A phase II biomarker-selected cohort was planned to receive the combination neoadjuvantly. That portion of the study was terminated prior to patient enrollment due to the withdrawal of industry support. Results: Six patients with metastatic CRPC were enrolled in the phase I cohort. They had received a median of 3 prior systemic therapies in addition to ADT (range 1-6). All patients completed the DLT period, and no DLTs were observed. The RP2D of ipatasertib, when given with darolutamide, is 400mg daily. Two patients (33%) had serious adverse events (SAEs) (diarrhea; grade 3) related to ipatasertib outside the DLT period. Two patients (33%) had SAEs unrelated to study drugs; pyelonephritis (one patient; grade 3) secondary to obstruction, and respiratory failure (one patient; grade 5) attributed to disease progression. Two (33%) patients had at least a 50% decline in PSA as the best PSA response, including 2 of 3 patients with known PI3K pathway alterations. Median PSA progression free survival (PFS) was 3.35 months (95% CI 3.06-NA). Median radiographic PFS was 2.91 months (95% CI 2.79-NA). Conclusions: Combination therapy with darolutamide and ipatasertib in CRPC is safe and a RP2D of ipatasertib was established. Toxicity was similar to the therapies given alone, and the most common treatment-related SAE was diarrhea. Partial response to combination therapy was seen in men with CRPC and known PI3K alterations. Clinical trial information: NCT04737109.