乌鸦传媒

Combining olaparib (Lynparza) with abiraterone acetate (Zytiga) as first-line therapy for biomarker-selected patients with metastatic castration-resistant prostate cancer significantly improved progression-free survival (PFS) versus either agent alone, according to findings from a small phase II trial presented at this year's Genitourinary Cancers Symposium.

In this exclusive 乌鸦传媒 video, Daniel Geynisman, MD, of Fox Chase Cancer Center in Philadelphia, who was not involved in the research, discusses results of the so-called BRCAAway trial.

Following is a transcript of his remarks:

BRCAAway was a randomized phase II trial looking at the addition of a PARP inhibitor, olaparib to abiraterone in men with metastatic castrate-resistant prostate cancer.

So the drug olaparib is approved as a single agent for men with castrate-resistant prostate cancer who have a homologous recombination repair mutation, most common being BRCA2, but there are others. And the FDA actually approved within the last year, three different combinations of androgen receptor signaling inhibitors such as abiraterone and enzalutamide [Xtandi] with PARP inhibitors.

But this was a smaller trial that looked at androgen deprivation therapy [ADT] with an androgen receptor signal inhibitor -- with abiraterone -- or with olaparib, or just olaparib by itself, which is the new part of this. And it also tried to get at the question of: [is] combining the two drugs upfront better than kind of doing sequential therapy, meaning starting with androgen deprivation therapy and abiraterone, and then in progression going to olaparib? And that question has not really been clearly addressed by the large phase III trials.

What they clearly showed, no question about it, is that in men with BRCA1 or 2 or ATM mutations (but primarily BRCA2, that was the vast majority of the patients in this trial), the combination, the triplet, the androgen deprivation therapy, abiraterone, and olaparib -- so you're continuing the ADT, but you're bringing in the abiraterone and olaparib together -- much better. The PFS more than doubled than just abiraterone by itself, or olaparib by itself.

That's really the key finding, that for men with metastatic castrate-resistant prostate cancer who are just starting a new hormone therapy, such as abiraterone, and who have a mutation, such as BRCA2, really both olaparib and abiraterone should be started. Because you're putting your best foot forward there rather than the sequential approach. Because although folks who did get the drug they haven't had did all right, some people never did get to that point. And so you may be missing an opportunity to receive an effective therapy.

And this is really consistent with what the guidelines are now, which is that if you have metastatic castrate-resistant prostate cancer and you have a homologous recombination mutation, you really should think about, let's call it triplet therapy. In other words, continuing androgen deprivation therapy, bringing in a new drug like abiraterone or enzalutamide, and then bringing in a PARP inhibitor. So it was really, I would say, practice-affirming.

The hard question and the hard situation now is that the field has changed, and we are using drugs like abiraterone. We're using [these] novel androgen receptor pathway drugs right upfront for hormone-sensitive prostate cancer. And so the group of patients that was meant to be and is meant to be in this kind of trial are folks who did not have those drugs initially and have developed castrate resistance, and then are moving on to that. So that population is rapidly shrinking.

So a lot of patients won't really fit that criteria that this trial looked at and that the large phase III trials looked at that got the approval for this. So it would be great to have an upfront trial for men who have hormone-sensitive prostate cancer and have a homologous recombination mutation and give them these triplets all the way upfront. So from the beginning.

That's a tough trial to do because it would require so many men. It would have to be randomized, it would have to be an international trial, and I'm not sure that will be done. Maybe it would be done through the cooperative groups. But that's really the next step.

I think as for PARP inhibitors in and of themselves, they clearly, clearly have a place. And actually if you look at this trial, a large proportion of men who were screened -- there were about 160 men who were screened -- like 60, well over 30% qualified, which actually I was surprised at. That's a very high number. Most of the time we think about homologous recombination mutation somewhere in, let's say the 20% range, this was well over 30%.

So it's a small sample size, maybe it's just sort of a sampling situation. But it just underscores the point that all men with prostate cancer really need to have both genomic and probably genetic testing to make sure we don't miss these mutations for which we have drugs.

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