Lutetium-177-PSMA I&T (Lu-PSMA) with radiosensitising capecitabine in patients with metastatic castration-resistant prostate cancer (mCRPC): results of phase Ia study.
Capecitabine at 1000 mg/m² with Lu-PSMA is safe in heavily pre-treated mCRPC patients, but further research is needed to confirm efficacy.
Where it sits
this study against the rest of the vipivotide corpusSummary and findings
This phase Ia study evaluated the safety and maximum tolerated dose of capecitabine combined with Lu-PSMA in 12 men with metastatic castration-resistant prostate cancer. The maximum tolerated dose was established at 1000 mg/m² with no dose-limiting toxicities. The PSA-50 response rate was 50% with a PSA-progression free survival of 4.7 months.
Abstract
<h4>Purpose</h4>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.<h4>Methods</h4>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<sup>2</sup> - 1000 mg/m<sup>2</sup>) 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.<h4>Results</h4>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<sup>2</sup>. 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.<h4>Conclusion</h4>Capecitabine 1000 mg/m<sup>2</sup> in combination with Lu-PSMA is safe and tolerable in heavily pre‑treated mCRPC. A dose‑expansion cohort is ongoing to further evaluate efficacy.
Background
The study addresses the potential for combining Lu-PSMA, a therapy for metastatic castration-resistant prostate cancer (mCRPC), with capecitabine, a known radiosensitiser. Previous research has shown capecitabine's effectiveness in enhancing radiotherapy in various solid tumors. This study is important as it explores a combination therapy approach in a heavily pre-treated mCRPC population.
Methods
This was a phase Ia, 3+3 dose-escalation study involving men with mCRPC who had previously been treated with at least one taxane and one androgen receptor pathway inhibitor. Participants were administered capecitabine at four dose levels (275 mg/m² to 1000 mg/m²) on days 1-14, with Lu-PSMA given on day 10 of a 42-day cycle, for up to six cycles. The primary endpoint was the maximum tolerated dose (MTD), while secondary endpoints included safety, PSA-50 and objective response rates, PSA-progression free survival, clinical and radiological progression-free survival, and overall survival.
Results
Twelve patients received at least one dose of Lu-PSMA, with a median age of 75. No dose-limiting toxicities were observed, establishing the MTD at 1000 mg/m². Common adverse events included nausea, fatigue, and diarrhea. The PSA-50 response rate was 50%, and the PSA-progression free survival was 4.7 months (95% CI 2.3-21.6). One patient achieved a partial response, and exploratory PSMA PET biomarker analyses were negative, likely due to the small sample size.
Interpretation
The study suggests that capecitabine at 1000 mg/m² combined with Lu-PSMA is safe and tolerable in a heavily pre-treated mCRPC cohort. While the PSA-50 response rate of 50% is promising, the small sample size limits the robustness of these findings. The lack of dose-limiting toxicities is encouraging, but the clinical significance of the PSA-PFS of 4.7 months requires further investigation in larger cohorts. The ongoing dose-expansion cohort may provide more insights into the efficacy of this combination therapy.
Key findings
- 12 patients received at least one dose of Lu-PSMA.
- Median age was 75.
- No dose-limiting toxicities occurred.
- MTD established at 1000 mg/m².
- PSA-50 RR was 50%.
- PSA-PFS was 4.7 months (95% CI 2.3-21.6).
Limitations
- small n=12
- single-site study
- short follow-up
- exploratory biomarker analyses negative
- heavily pre-treated cohort