What was the primary objective of the PEACE-3 trial, and why was this combination strategy important to test?
PEACE-3 had radiographic progression free survival as its primary objective with overall survival as a key secondary endpoint. Enzalutamide and radium-223 independently demonstrated an overall survival benefit in first and second line in metastatic castration resistant prostate cancer. As mechanisms of action are different, the rationale to combine is to try to improve the benefit of every drug separately.
What do the final overall survival results tell us about adding radium-223 to enzalutamide?
The combination of enzalutamide plus radium-223 demonstrated an overall survival benefit, significant and probably clinically meaningful, with a hazard ratio of 0.76 and a confidence interval inside 1.0, the upper limit. The p-value was below the significance threshold previously fixed and the median overall survival was 38 months for the combination and 32.6 for the control arm. These are important results in terms of statistical benefit but also in the clinical application.
How did the combination impact safety, particularly regarding bone health and fracture risk?
The combination slightly increases the toxicity incidence, adverse event incidence. If we see grade 3-5 drug-related adverse events they increase from 19% in the control arm to 29% in the combination. There were more serious drug-related adverse events but it’s important to say that no individual grade 3-5 adverse events increases more than 5% in the combination. There were no drug-related deaths reported in any of the arms.
Regarding bone health, it’s true that the incidence of fractures was higher in the combination arm – 27% versus 14% – but if we see at grade 3-5 fractures the difference was relatively small. The incidence of fractures didn’t seem to impact the survival of patients. If you see the curves, the curves crossed before 18 months and in the first 12 months there were no differences between the incidence of fractures between arms. So I think it’s a point of caution but it doesn’t have to impact in the applicability of the combination.
Which patients appear most likely to benefit from this treatment approach?
The study population included patients having received ADT alone or ADT plus docetaxel in the hormone sensitive setting. So this is the target population. But some patients had received also abiraterone in the first line so probably we could apply this treatment not only to patients not having received an ARPI but patients having received abiraterone could be also a good target for the combination, even considering in other patients having received other ARPIs.
So we don’t know if there are no patient candidates to this treatment, we don’t have any biomarker, any other factors to consider. It’s true that if we analyse subgroups older patients and patients with some factors related to bad prognosis seem to benefit less but a clear conclusion could not be made in this sense. So any patient in first-line metastatic castration resistant prostate cancer with bone metastasis, specifically patients not having received enzalutamide, apalutamide or darolutamide, should be good candidates.
How might these findings influence treatment sequencing or standards of care in metastatic castration-resistant prostate cancer?
For patients not having received an ARPI in the first line, it’s clear that the combination of enza plus radium-223 shows a clear benefit, so in this case. To me, I don’t if it’s the best but it’s a good option for them. When the patients had received a previous ARPI in the hormone sensitive setting, probably a subgroup of them could benefit from the combination. Maybe we can avoid or delay the use of chemotherapy, especially in frail patients, probably unfit for chemotherapy, but at the end the most important point is benefit patients not only in survival but in safety and quality of life. So if you can get all of this with the early application of the combination, it could be a good goal for patients.
Is there anything else you would like to add?
Yes, I’d like to remark on the involvement of patients in the clinical trials design and clinical decisions regarding best options for them. I think it’s a very important point. We always speak about it but I think it’s necessary to implement in practice sooner than later.
