Prostate Cancer Advances Include Potential for PARP Inhibitors

Celestia Higano, MD

Celestia Higano, MD

The treatment of prostate cancer is rapidly progressing on several different fronts, says Celestia Higano, MD, who discussed several of the the latest advances at the 2017 Interdisciplinary Prostate Cancer Congress (IPCC).

“I want the community to have a sense of the very rapid change of pace of prostate cancer therapy. I hope to spread the message of what is changing, why is it is changing, what has been shown in evidence-based therapies, and what is still experimental,” said Higano, MD, professor of medicine and urology at the University of Washington, and a member of the Clinical Research Division at Fred Hutchinson Cancer Research Center.

OncLive: What has the latest research shown about the use of docetaxel in prostate cancer?

In an interview with OncLive at the IPCC, Higano discussed the early use of chemotherapy, the potential for PARP inhibitors, and the evolving role of radium-223 in prostate cancer.Higano: [At the IPCC] I wanted to relay the relatively new information about the addition of docetaxel to standard hormonal therapy and the survival benefit that has been seen, at least in patients with high-volume disease. Although, another study that was done that showed the same benefit did not separate out by how much disease there was. The bottom line is that this definitely changes the paradigm for treating patients with newly diagnosed, hormone-sensitive prostate cancer.

What impact has docetaxel made here?

What is the role of PARP inhibitors in prostate cancer?

There are other trials that will be read out later this year, probably at ASCO 2017, that will be comparing hormone therapy to hormone therapy with abiraterone acetate (Zytiga). And certainly, ADT and abiraterone is probably going to be a less toxic regimen than ADT plus docetaxel, so it is going to give us a lot to think about going forward. These 2 trials have not been compared head-to-head with docetaxel plus ADT, and maybe that is where we need to go with this, but it will definitely make us all scratch our heads about what to do if the trials are positive with abiraterone added to ADT.For the first time, docetaxel showed a very large difference in median overall survival in the patients who received it compared to hormone therapy alone. So, this is very new—it is one of the biggest improvements in survival that we've seen in oncology. I think that, as a medical oncologist, if we are using docetaxel earlier in the course of prostate cancer we do have to be a little cautious, though, about what impact this might have down the line. We have usually used docetaxel for metastatic castration-resistant disease, and now that we are using it for those who are metastatic hormone-sensitive disease—particularly in the high-volume patients—it might not work as well. There are some data that suggests that this happens in the castration-resistant setting, so we are just going to be cognizant of how we place docetaxel in a disease. There is some evolving information that we are getting in respect to drugs that can be used, and the kind of results we have seen recently with using PARP inhibitors in patients with so-called DNA damage alterations. The fact that approximately a quarter of the patients with metastatic prostate cancer have been shown to have these alterations is important because the use of an agent like a PARP inhibitor is a different treatment paradigm—as we have not used them before in this disease.

What results have been seen with PARP inhibitors?

What has been seen with isotope therapy?

If we know somebody has DNA damage alterations, I think we are going to start going the route of PARP inhibitor and/or platinum or platinum-like agents like carboplatin, which have also been shown to be effective in patients with ovarian cancer with DNA repair defects. We are assuming that they are going to be equally effective as PARP inhibitors in prostate cancers, but that still has not been shown yet.In one trial, 14 out of 16 patients responded to olaparib. The 16 patients all had DNA repair alterations. That is a very high response rate, it is a small study and we do not have survival data but anecdotally, many of us who frequently treat prostate cancer have used a PARP inhibitor and had some prolonged, very good responses in patients who looked like they had pretty bad disease. The isotope that I discussed was radium-223, which is an alpha emitter that was shown in a phase III trial to extend survival. Other radioisotopes that we have available to us, samarium and strontium, tend to be used—if used at all—toward the end of life when we are trying to quickly palliate bone pain. Radium-223 is a very different kind of agent—trials have shown there is a survival advantage in those who got radium in addition to best supportive care.

How do you see the future of radioisotope therapy progressing?

So, we need to think of using radium-223 earlier in the disease, not at the end, considering it takes 5 months to take all 6 doses. And, we need to now look at some combination trails because radium only goes to bone, and if a patient has disease outside the bone it would be great to understand what a combination—such as radium-223 plus abiraterone—will do for those patients. There is a phase III trial that is ongoing looking at abiraterone versus the combination of abiraterone and radium-223. That trial is fully accrued and hopefully in the next few years we will see results. One of the things I did caution was that we have studied radium-223 in combination with docetaxel, and we found that there can be some significant myelotoxicities that were perhaps, a little unexpected. This is because, in general, radium-223 is not very myelotoxic at all. It is not really recommended that people combine docetaxel with radium-223 right now, but we are going to learn how to better use the combination of radium-223 and chemotherapy with more trials. Right now, I wouldn’t suggest that oncologists use this outside of a clinical trial setting, it could be potentially dangerous.