Combined Testosterone Therapy with Olaparib in Patients With Metastatic Castration-Resistant Prostate Cancer – Michael Schweizer

September 20, 2021

In this UroToday discussion between Alicia Morgans and Michael Schweizer, they discuss a single-center phase II trial that combined testosterone therapy with olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC). Dr. Schweizer discusses why he and his team were interested in this study. Dr. Schweizer mentions preclinical observations in cancer cell lines, that mimic the castrate-resistant growth, that exposing them to high-concentration testosterone can lead to a paradoxical anti-tumor effect. They discuss the safety of the treatment.  Dr. Schweizer summarizes his study by discussing how bipolar androgen therapy plus olaparib has a strong efficacy signal, it appears safe, and definitely warrants further study.

Biographies:

Michael Schweizer, MD, Medical Oncologist, Associate Professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA

Alicia Morgans, MD, MPH Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts.


Read the Full Video Transcript

Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I am so excited to have with me here today, Dr. Michael Schweizer, who is an Associate Professor of Medical Oncology at the University of Washington and the Fred Hutchinson Cancer Center in Seattle, Washington. Thank you so much for being here with me today, Dr. Schweizer.

Michael Schweizer: Yeah, it's a pleasure to be here. Thanks.

Alicia Morgans: Wonderful. I wanted to talk with you a little bit about your recent presentation at ESMO 2021, where you really described, I think, a groundbreaking combination of testosterone therapy and olaparib in patients with metastatic castration-resistant prostate cancer. Can you tell us a little bit about your study?

Michael Schweizer: Yeah. So we've had a lot of interest over the years in developing high-dose testosterone as a therapy for patients with metastatic castrate-resistant prostate cancer. This work is based on a number of preclinical observations that in cancer cell lines, that mimic the castrate-resistant growth, that exposing them to high concentration testosterone can lead to this paradoxical anti-tumor effect. One of the mechanisms underlying this that has been described by multiple groups is that high doses of testosterone and other androgens can actually induce DNA damage in the context of cells expressing high levels of the androgen receptor.

Taking this one step further, Pete Nelson, one of my collaborators at the Fred Hutch, his lab did some preclinical work looking at the combination of high-dose testosterone in combination with the PARP inhibitor olaparib, to evaluate whether or not those two agents might synergize, or at least be additive, in terms of their anti-tumor effect together. And that's exactly what they saw, essentially, that these effects were more pronounced with a combination of both BRCA null as well as BRCA intact prostate cancer models.

We've also seen in clinical studies testing bipolar androgen therapy, this form of high-dose testosterone that we've been testing in several clinical trials, that in patients that have evidence of mutations in DNA damage repair genes, that they appear to actually have better responses to bipolar androgen therapy than those who do not have mutations in those genes.

And so it was these observations that really set the stage for this clinical study that we ran to look at whether or not the combination olaparib plus bipolar androgen therapy, or BAT, would be effective in patients with metastatic castrate-resistant prostate cancer. The study was pretty straightforward. We enrolled patients who had metastatic castrate-resistant disease and who were proposed abiraterone and or enzalutamide. We also require that they not have any cancer-related pain. This has been an eligibility criterion that was included in all of our BAT studies, mainly because we are worried that, in theory, if there was a cancer flare-up, that this could cause pain and other adverse events, and so we tried to select sort of a lower-risk patient population.

But patients that were eligible, enrolled and got the combination of testosterone enanthate once in one inner muscular injection every 28 days in combination with olaparib, and they continued this until radiographic disease progression. The primary endpoint was PSA 50 response rate at 12 weeks or a PSA decline of at least 50% or greater. As far as the demographics, all patients received abiraterone and/or enzalutamide, and about a third got both agents. Overall, looking at the primary response endpoint, we had 30 patients that were response eligible and continued on treatment through the initial 12-week period of time. And out of that 30 patient population, we saw 14 responses. So a response rate of 47% overall.

One interesting feature of this study was that we mandated that half the patient population have a mutation in a DNA damage repair gene, whereas the other half were required to not have one of these alterations. And interestingly, we saw that response rates in those with a DDR alteration versus those that did not have one were identical. 7 out of 15 and 7 out of 15. And so, it showed that this combination appears to be effective regardless of what happens with the DDR status for those individuals.

Looking at progression-free survival, we saw that the median PFS for this response evaluable cohort was 12.39 months, which compared pretty favorably to some of the other studies that have been done. So just to put into context, in a trial that we conducted looking at bipolar androgen therapy versus enzalutamide in a similar patient population, patients that got BAT had a median progression free survival of a little less than 6 months. And so this clearly looks longer than that, granted, comparing across trials can be brought with difficulty and problems.

Interestingly again, when stratifying results based on the DNA damage repair gene mutational status, we saw the patients that had a DDR gene alteration actually had a trend towards worse median progression-free survival, at 8.49 months, versus 14.56 months in those that had no evidence of a DDR alteration. Likewise, when you looked at radiographic responses, we saw high radiographic response rates in the 13 patients that were response evaluable, per RECIST criteria, and out of these patients, we saw 8 responses or 62% with a response. And again, we didn't see any clear differences between those with or without a DDR alteration.

Honing in on the specific mutations that were present in those 15 patients that had a DDR alteration, we saw that there was a smattering of the ones that you'd normally expect, but I think it is worthwhile pointing out that the patients that had a BRCA2 alteration only accounted for 19% of the total patient population. And these are the ones that have really looked to be the most likely to benefit from treatment with PARP inhibition based on prior studies. We also, of note, saw high rates of responses in those with ATM mutations, CDK12 mutations, and other genes that didn't necessarily show high response rates in some of the other studies testing rucaparib, olaparib, and some of the other prostate cancer PARP inhibitors that are being developed.

So yeah, I think the results have been encouraging so far, and we are in the process of trying to figure out if there is a way to move this forward in additional larger randomized studies since based on the results we've seen, that certainly justifies an additional study.

Alicia Morgans: I think it certainly justifies that this is a safe approach, which, of course, is the first question in most people's minds when they are talking about metastatic CRPC. But also, it's interesting that the PFS was longer in patients without DDR mutations. Can you comment on that, and maybe comment on it in the context of the breakdown of the mutations that you had in this population?

Michael Schweizer: Yeah. I think it's an interesting point. Typically, when you think about using a therapy that is designed for a certain genomic sub-group, such as a PARP inhibitor, that you'd think that those patients would fare the best in a clinical study that has a more heterogeneous patient population. But we didn't see that. I think it may be that when you look back in some of the other studies that were testing PARP inhibitors, the benefit was primarily in those with BRCA2 mutations, and that was a relative minority in our patient subset. The other issue might be that these patients with mutations in DNA damage repair genes just have more aggressive biology and that at that point, that trumped the overall efficacy, in terms of progression-free survival, that we saw here.

Alicia Morgans: But so interesting that these patients might get a benefit, those patients without a DNA repair defect mutation might get a benefit, from olaparib if they have some testosterone alteration. We had some opposite information, but potentially still consistent if we're talking about altering testosterone signaling when we saw the combination of abiraterone and olaparib and saw responses even among wild-type patients. So there might be something within this androgen signaling pathway, that whether we upregulate, downregulate, or overwhelm, perhaps, with this bipolar androgen therapy that allows patients who don't have these alterations to actually be sensitive to olaparib treatment. I think it's really intriguing and would love to hear your thoughts.

Michael Schweizer: Yeah, it is. It seems somewhat contradictory. Going back to some of the preclinical studies that I mentioned earlier, there was some data in one of our earlier papers where we looked at transcript levels of some of the course homologous recombination repair genes and how they changed after response to either exposure to castrating conditions or in response to super physiologic androgens. And you see that in both conditions, you actually see that there is a downregulation of these HR genes, whether it's with castrating therapies or with high-dose androgens. And in fact, by giving them high-dose androgens, you saw actually a higher suppression of those transcripts. So, it's a little bit counterintuitive, but again, it provides sort of some mechanistic understanding as to why both of these things may synergize with something like olaparib, in addition to the fact that testosterone probably works, at least in part, through inducing DNA damage itself.

Alicia Morgans: Really fascinating and I think we are really only just beginning to understand how these different pathways work together. And I sincerely appreciate that your group is helping to really educate all of us on how high doses of testosterone might be used to really harness the power of things like PARP inhibitors, but other approaches as well, of course, with the other work that you're doing. If you had to summarize this particular abstract and this study, what would it be?

Michael Schweizer: Yeah. I would say that based on this study, bipolar androgen therapy plus olaparib appears to have a strong efficacy signal.  It appears safe, and I think that overall, this is something that warrants further treatment. So, hopefully, stay tuned and we can roll out larger randomized studies and get this to the point where we can offer this as a standard of care at some point.

Alicia Morgans: Well, I am certain that patients would love to see an approach that involves high doses of testosterone, and certainly physicians, if safe, would love to be able to provide that for their patients. So we sincerely appreciate that you and your team are continuing to pursue this, and not only pursue it in isolation, but in combinations, like the one that you just presented at ESMO. Thank you so much for your continued efforts and certainly for taking the time to talk with me about it today.

Michael Schweizer: Yeah, absolutely. It's great talking to you, okay? Hopefully, we can do it in person next time.
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