Background: NOX66 is a new formulation of the small molecule, idronoxil. The primary mechanism of action of idronoxil stems from its binding to the transmembrane enzyme ENOX2 expressed on cancer cells, resulting in reduced S1P and increased ceramide levels, thereby promoting apoptosis. Additional intracellular effects include the inhibition of DNA repair mechanisms. There is growing evidence that S1P is a promotor of tumour resistance to immune cell infiltration, highlighting NOX66’s potential to modulate the immune response against cancer. Methods: This two-part phase 1b open-label study enrolled patients with late-stage progressive mCRPC. Part 1 was a dose-escalation safety assessment of three doses of NOX66 (400 mg, n = 4; 800 mg, n = 6 and 1200 mg, n = 15) administered daily for 14 days with radiation therapy (20 Gy) delivered in 5 fractionated doses to one or more symptomatic lesion/s. Part 2 was an expansion cohort with NOX66 at 1200 mg in conjunction with radiation therapy. The primary endpoint of safety was assessed by the frequency and grade of treatment-emergent adverse events (TEAEs). At 6 weeks, 3- and 6-month follow up, treatment response was assessed radiographically by RECIST1.1 and by PSA >50% reduction. Results: 25 patients received and completed treatment. TEAEs considered related to NOX66 alone were mild (Grade 1) cases of dry mouth and oral mucositis; mild (Grade 1) fatigue was considered related to both NOX66 and radiation. None of the 21 Grade ≥3 TEAEs were considered related to NOX66. At 6 months, of the 15 evaluable patients by RECIST1.1, 9 had SD and 1 had PR and these same patients had maintained this response from 3 months. Five of the 16 PSA-evaluable patients achieved a PSA response (61-98% PSA reduction) at 6 months, which again was maintained from 3 months. Conclusions: NOX66 in combination with low-dose radiation therapy was found to be safe and well tolerated with promising signals of durable efficacy in patients with late-stage mCRPC. Responses of lesions outside the radiation field are being reviewed. Clinical trial information: NCT03307629.