Lutetium-177-PSMA I&T (Lu-PSMA) with radiosensitising capecitabine in patients with metastatic castration-resistant prostate cancer (mCRPC): results of phase Ia study

Abstract Purpose Lu-PSMA is an effective therapy for mCRPC. Capecitabine is an established radiosensitiser in several solid tumours and may enhance therapeutic response when combined with radioligand therapy. We evaluated the safety and maximum tolerated dose (MTD) of capecitabine with Lu-PSMA in a heavily pre-treated mCRPC cohort. Methods Men with mCRPC previously treated with ≥ 1 taxane and ≥ 1 androgen receptor pathway inhibitor, and deemed suitable for Lu-PSMA on PSMA-PET, were enrolled in a 3 + 3 dose-escalation study. Capecitabine was administered at four dose levels (275 mg/m 2 – 1000 mg/m 2 ) on days 1–14, with Lu-PSMA on day 10 of a 42-day cycle, for up to six cycles. The primary endpoint was the MTD; secondary endpoints included safety, PSA-50 and objective response rates (RR), PSA-progression free survival (PFS), clinical and radiological PFS, and overall survival (OS). PSA was assessed every two weeks; imaging every 12 weeks. Results 12 patients received at least one dose of Lu-PSMA. Median age was 75. No dose-limiting toxicities occurred, establishing the MTD at 1000 mg/m 2 . Common treatment-related adverse events were nausea, fatigue, and diarrhoea. Across dose levels, the PSA-50 RR was 50%, and PSA-PFS was 4.7 months (95% CI 2.3–21.6). One patient with measurable disease achieved a partial response. Exploratory PSMA PET biomarker analyses were negative, likely limited by small sample size. Conclusion Capecitabine 1000 mg/m 2 in combination with Lu-PSMA is safe and tolerable in heavily pre‑treated mCRPC. A dose‑expansion cohort is ongoing to further evaluate efficacy.