First randomised trial of Lu-PSMA in mCRPC progressing after docetaxel

TheraP is the first (non-blinded) trial comparing Lu-PSMA to an active therapy with cabazitaxel in men with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel. Results demonstrated that Lu-PSMA has high activity and relatively low toxicity, consistent with the results of prior single-centre phase 2 data. Lu-PSMA appears to represent a favourable treatment option compared with cabazitaxel in a selected population with high PSMA expression.

In the last 2 decades, several life prolonging therapies have been approved for the treatment of mCRPC, including docetaxel, cabazitaxel, abiraterone, enzalutamide, sipuleucel-T, and ²²³Ra. Recently, ¹⁷⁷Lutetium-PSMA-617 (Lu-PSMA) has been developed. Lu-PSMA is a radiolabelled small molecule which binds with high affinity to prostate-specific membrane antigen (PSMA), a cell surface glycoprotein overexpressed in metastatic prostate cancer. This enables delivery of high doses of radiation with high targeting specificity to sites of prostate cancer. Encouraging efficacy and safety of Lu-PSMA in patients with mCRPC progressing on docetaxel have been demonstrated in non-randomised trials, primarily compassionate access trials from Germany, where this therapy was developed [1].

In TheraP, 200 patients with progressive disease (rising PSA and PSA ≥20 ng/mL) were 1:1 randomised to Lu-PSMA (8.5 GBq IV every 6 weeks) or cabazitaxel (20 mg/m² every 3 weeks) [2]. Primary endpoint of the study was PSA response, defined by PSA reduction ≥50% from baseline (PSA50-RR). Secondary endpoints included PSA progression-free survival (PFS), and adverse events.

Primary endpoint after a median follow-up of 13.3 months was 66% in the Lu-PSMA arm versus 37% in the cabazitaxel arm. Absolute PSA50-RR difference between Lu-PSMA and cabazitaxel was 29% (95% CI 16%-42%; P<0.0001) in favour of Lu-PSMA. Preliminary results of the secondary endpoint PSA PFS also showed benefit with Lu-PSMA (HR 0.69; 95% CI 0.50-0.95; P=0.02). Improvements in overall survival have not yet been demonstrated.

Adverse events grade 3-4 were observed in 35% of patients in the Lu-PSMA arm compared with 54% in the cabazitaxel arm.

1. Heck MM, et al. Eur Urol. 2019; 75: 920-926.
2. Hofman MS, et al. ASCO Virtual Meeting, 29-31 May 2020, Abstract 5500.

Posted on 17 September 202029 February 2024