Enzalutamide treatment boosted by Radium-223 in mCRPC

Prof Silke Gillessen - Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

My study is a randomised study, a phase III study, and, importantly, it’s an investigator initiated study. It’s called PEACE-3, it’s a study from this PEACE consortium, and it’s in reality an EORTC study in collaboration with a lot of cooperative groups. So it was really nice, the collaboration with everyone. The question was if in the setting of first-line mCRPC, so for patients who progress on ADT alone without having had a prior RP, the addition of radium to enzalutamide gives a benefit for rPFS, that was our primary endpoint, but also for overall survival, versus enzalutamide alone, which is the standard of care.

That was really a very nice result that the rPFS that we had targeted with a 32% improvement had 31% improvement for radiological progression free survival and death. So that was quite interesting. In more concrete numbers the median OS went from 16.4 to 19.4 months and we saw also in the log-rank test, again with a hazard ratio of 0.69, a benefit for overall survival. The overall survival curves are crossing in the beginning so the log-rank test is not an ideal test so that’s why we decided to go to the final overall survival analysis.

Interestingly, also the time to next systemic treatment was prolonged in the combination arm. What we also saw is that the time to pain progression was no different and also the time to first symptomatic skeleton event was not different. But one really important point is that we made the use of bone targeted agents mandatory. This is something that is a very important message that we got out of this study and also already with ERA 223 that had a similar design but used abiraterone together with radium. We saw an increased risk for fractures in the combination arm but even for enzalutamide alone without bone protecting agents the risk was about 15% of fractures. So it’s really important that we think about giving bone protecting agents to patients with mCRPC. This is another important message from this study.

What toxicities were experienced?

So for the safety, it’s really interesting what we saw in both arms. The most frequent term that was used is hypertension and it was about 30% in both arms and that’s probably caused by enzalutamide. We have to be really careful monitoring our patients for hypertension because the really nice thing is that now we have a long overall survival also in that situation but that means that we have to take care of the metabolic side effects that we are inducing. It's important, that can be done by a GP, it can be done by the oncologist, but it’s really important to measure hypertension, blood pressure. The patients can do it on their own at home; however you’re doing it but you have to monitor hypertension.

For the addition of radium we saw myelotoxicity as expected. We had in total drug related adverse events grade 3 or higher we had 19% in the enzalutamide arm and it went to 28% in the combination arm, so about 10% more so we have to take care of that. There was more fatigue, these are the things that came out as grade 3 and 4 toxicities. There was also more diarrhoea, as we expected, but fortunately not in that high grade.

What impact could this have?

What is nice is that we have now a new potential treatment option for first-line mCRPC. Remember, these were patients progressing on ADT so not patients that had the current standard of care of ADT plus an RP. I think that’s an important limitation but still we know that globally a lot of patients still get ADT alone. I really hope that that’s going to change in the next years but this is real life evidence that we have for the moment. So for these patients that would fit the inclusion criteria and are progressing on ADT alone, have bone metastases, I think this is a new valid option to discuss with your patients.