Praful Ravi, MBBChir, MRCP, on High-Risk Localized Prostate Cancer: Docetaxel With ADT and Radiotherapy

In this work, we did an individual patient data meta-analysis of trials looking at docetaxel with ADT (androgen deprivation therapy) and radiotherapy for high-risk localized prostate cancer. Now, we know as a way of background that radiotherapy plus long-term ADT for about two years is a standard of care for the treatment of men with high-risk localized prostate cancer. More recently, the addition of abiraterone has improved outcomes even further in men with very high-risk disease in the STAMPEDE trial. Now, docetaxel is a chemotherapy drug that has proven benefit in metastatic and advanced prostate cancer. It has been looked at in a series of trials in the localized setting, but mixed results have been seen. So what we set out to do here was to collate the data available within the ICECaP repository of trials looking at docetaxel and perform the individual patient data meta-analysis. Specifically, we wanted to see whether men with very high-risk disease—so we've actually done prior work from ICECaP showing that within high-risk prostate cancer, patients with two to three high-risk factors—so Gleason 8 or above, PSA greater than 20, clinical T3 or T4 disease, and/or clinical node-positive disease—these are the patients that do poorest with radiotherapy and long-term ADT. So we wanted to see (A) is docetaxel doing anything overall, and (B) specifically, is it beneficial in the very high-risk patients. So what did we do? We had four randomized trials available within the ICECaP repository, and we classified patients as either high-risk disease with one risk factor or very high-risk disease with two to three. And we primarily looked at the following five outcomes: MFS (metastasis-free survival), OS (overall survival), EFS (event-free survival), prostate cancer death, and time to metastasis. Overall, there were around 1,700 patients included—around 650 had high-risk disease (so one high-risk factor), and the remainder, around 1,000, had two to three high-risk factors (very high-risk disease). In the overall population—so all 1,700 patients—there was not a significant benefit to the addition of docetaxel to radiotherapy and ADT for high-risk localized disease. In terms of metastasis-free or overall survival, the hazard ratios were less than one, but it was not significant—the boundary crossed one. In very high-risk patients compared to high-risk patients, there did appear to be a greater benefit for adding docetaxel. So the hazard ratios in the high-risk population for MFS, OS, and other endpoints were in the 0.9 range, and for the very high-risk patients, they were in the 0.7–0.8 range, suggesting a greater benefit or a potential greater benefit for docetaxel in the very high-risk patients. Now, this was not statistically significant in terms of an interaction significance, but clinically there does appear to be a greater benefit, maybe in these very high-risk patients. So where do we take this forward? Well, right now standard of care for patients is ADT for two years, radiotherapy, and maybe abiraterone or another androgen pathway inhibitor. Now, could we do some biomarker work in the very high-risk patients to find out who might stand to benefit most from something like docetaxel? And can we then use that to design a trial to evaluate intensification beyond just ADT plus radiotherapy—maybe even an ARPI and adding docetaxel? I think that's where we would look to take this next. Docetaxel is a cheap drug. It's very widely used. It's easily available. So this would be a natural extension to this work.