177Lu-PSMA-617 outperforms cabazitaxel in men with metastatic castration-resistant prostate cancer
Previously, results from the phase II TheraP trial demonstrated that in men with metastatic castration-resistant prostate cancer progressing after docetaxel, 177Lu-PSMA-617 provided a stronger progression-free survival benefit than cabazitaxel, with less toxicity. Now, after 36 months of follow-up, it was reported that 177Lu-PSMA-617 also provides a comparable overall survival benefit to cabazitaxel.
177Lu-PSMA-617 is a radiolabelled small molecule that binds to prostate-specific membrane antigen (PSMA), enabling the delivery of high doses of β radiation to tumour sites. Previous results of the phase II TheraP trial demonstrated that in men with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel, patients assigned to LuPSMA had significant improvements in PSA response rate (66% vs. 37%), RECIST response rate (49% vs. 24%), progression-free survival (HR 0.63), less grade 3-4 toxicities (33% vs. 53%) and better patient-reported outcomes as compared to those assigned to cabazitaxel. At ASCO 2022, results of the secondary endpoint of overall survival (OS) with mature follow-up, both for trial participants and those initially excluded because of low PSMA-expression or discordant disease on imaging with PSMA-PET and FDG-PET, were presented.
Study Design
Eligibility for the TheraP trial required mCRPC progressing after docetaxel, PET imaging with 68Ga-PSMA-11 that showed high PSMA-expression (at least one site with SUVmax≥20), and 18F-FDG demonstrating no sites of disease that were FDG-positive and PSMA-negative (discordant disease). Participants were randomly assigned to treatment with LuPSMA (6-8.5 GBq every 6 weeks, up to 6 cycles) vs. cabazitaxel (20mg/m2 every 3 weeks, up to 10 cycles). OS was analysed by intention-to-treat and summarised by restricted mean survival time (RMST) to account for non-proportional hazards.
Results
In total, 291 patients were screened, of which 200 were eligible and randomly assigned LuPSMA (N= 99) or cabazitaxel (N= 101). Furthermore, 80 of 291 patients (27%) registered after initial eligibility were excluded after PSMA/FDG-PET (N= 51 SUVmax < 20, N= 29 discordant), with follow-up available in 61 of the 80 patients (76%). In the cabazitaxel arm, 15 men withdrew from the trial after randomisation. After a median follow-up time of 36 months (data cut-off December 31, 2021), death was reported in 70/101 assigned cabazitaxel, 77/99 assigned LuPSMA, and 55/61 excluded after PSMA/FDG-PET. Post protocol treatments among those assigned cabazitaxel included cabazitaxel in 21% and LuPSMA in 20%. Among those assigned LuPSMA, post protocol treatment included additional LuPSMA in 5% and cabazitaxel in 32%.
As part of longer follow-up, PFS was reanalysed and remained strongly in favour of LuPSMA (HR[95%CI]: 0.62[0.45-0.85], p= 0.0028). There was a similar HR for radiographic PFS (0.65) and PSA-PFS (0.60). As the treatment effect is not constant with respect to time, biostatisticians elected to use restricted mean survival time (RMST) in an updated statistical analysis plan for OS. Overall survival was similar in those randomly assigned LuPSMA versus cabazitaxel (HR[95%CI]: 0.97[0.70-1.4], p= 0.99). The RMST to 36 months was 19.1 vs. 19.6 months, respectively (difference -0.5, 95%CI -3.7 to + 2.7). Importantly, no additional safety signals were identified with longer follow-up. Among 61 men excluded by imaging with PSMA/FDG-PET before randomisation, RMST to 36 months was 11.0 months (95%CI: 9.0-13.1), noted to be much shorter than the patients included in the study (18.8 months).
Conclusion
The TheraP data support the choice of 177Lu-PSMA-617 over cabazitaxel for patients with PSMA-positive, progressive mCRPC after docetaxel and androgen-receptor pathway inhibitor, on the basis of its higher PSA response rate, greater PFS benefit, quality of life benefits, favourable safety profile and dosing schedule, and similar survival outcomes. Survival was considerably shorter for patients excluded on PSMA/FDG-PET with either low PSMA-expression, or discordant disease.
Reference
Hofman MS, et al. TheraP: 177Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel—Overall survival after median follow-up of 3 years (ANZUP 1603). Presented at ASCO 2022; Abstract 5000.
