Rana McKay: Thank you so much for having me. It's an absolute pleasure.
Neeraj Agarwal: So much is happening from genomic testing perspective in patients with metastatic prostate cancer. Today, we will like to delve into metastatic castration-resistant prostate cancer, now called as metastatic androgen pathway modulation-resistant prostate cancer, because nobody really liked the word castration. So I'm so glad we have been able to get rid of this word castration. So androgen pathway modulation-resistant prostate cancer and genomic testing.
Rana McKay: Yes.
Neeraj Agarwal: So your take.
Rana McKay: APMR, yes. This is the new nomenclature that's being applied, APMS, APMR, more patient-friendly terminology, and also integrating the role of the ARPIs that have just now utilized across the entire continuum. So it's interesting as we've evolved over the last decade of understanding the genomic drivers of prostate cancer and opportunities to find vulnerabilities based off of those that could be targeted. And I think the first foray in that was PARP inhibitors, of course, looking at monotherapy and evolving to look at combination therapy in the castration-resistant. Oh, there I go. The APMR setting. Okay. But I will say that for individuals that in the modern era are now APMR, routine NGS testing for all patients, including both germline and somatic tumor flow profiling is an absolute must. And even though patients may have had testing in the APMS setting or hormone-sensitive setting, may have had testing on a old prostate specimen from a decade prior, retesting to assess acquired resistance through an HR pathway alteration is critical. So I think for individuals that have APMR, they all should undergo both somatic and germline testing.
Neeraj Agarwal: Talking about somatic testing, tissue or metastatic tissue or ctDNA, your preference? Should we do both? One is enough. What is your take?
Rana McKay: Very good question. So I think the preference is tissue if available, but understanding the nature of the disease that we treat in its bone predominance and in its evolution from time of diagnosis to metastasis development, in some scenarios, tissue may not be available. And just because tissue is not available doesn't mean you lose out on an opportunity to test. So I would say tissue prioritize and if not available, a ctDNA test. I think ctDNA testing can also be helpful in repeated testing. Maybe somebody had archived tissue testing and then their tumor is evolved and you may want to repeat a test, ctDNA is helpful. I think the issues with ctDNA testing is that you need a certain amount of critical tumor burden to actually have a positive test. Sometimes a negative test is not necessarily a negative test, just a not detectable test. And I think sometimes CHIP alterations can impact our ability to accurately call HRR alterations. Many CHIP clonal hematopoiesis of indeterminate significance or indeterminate prognosis, they can happen in the HRR pathway. Yeah. ATM is notorious for that.
Neeraj Agarwal: So talking about the implications of positive results, HRR mutation positive. So if you get HRR mutation presence in those results, or MSI high, or DMB high, or RB1 loss, PTEN loss, what are the implications on treatment and monitoring?
Rana McKay: Very good question. So I think definitely the presence of some of these alterations is prognostics. Certainly if somebody's got RB1, that is a negative prognostic factor, same as PTEN. RB1, when you see it evolve, some concern is for lineage plasticity. Is there neuroendocrine prostate cancer that's evolving or about to evolve? I think there's been data to suggest that patients that have tumor suppressor gene alterations, namely PTEN, there can be kind of a dyssynchrony between PSA and imaging, mainly more in the hormone-sensitive setting. But I think in these individuals, maybe you want to scan a little bit more frequently than you otherwise would. So I think beyond the therapeutic implications, there can be implications with regards to prognosis, monitoring, at first glance on an NGS report.
Neeraj Agarwal: So we know about the implications on treatment of MSI-high, TMB-high mutation status, TMB 10 or more, MSI high, about 5% of these patients, they can have pretty good response to pembrolizumab. Coming back to the HRR mutations, what is the take on monotherapy versus dual therapy? When should we apply them? Especially in those patients who have not really truly progressed on a ARPI. So with increasing use of ARPIs in localized prostate cancer setting or biochemical recurrence setting, when we are using limited duration ARPI, many of these patients may not have disease progression on an ARPI or may not have even exposure to ARPI. How do you approach those patients if they have HRR mutations?
Rana McKay: Very good question. So I think that there were several studies that looked at combination PARP inhibitors with ARPIs. Most of those studies, nearly all of them were conducted in people that were ARPI naive. So I think if somebody is ARPI naive or ARPI pretreated, but not ARPI resistant, I think thinking about the combination certainly makes sense for somebody with an HRR alteration, given the label for enzalutamide/talazoparib from the TALAPRO-2 study, I think makes sense. Now, if somebody is ARPI exposed and progressed on an RP, which is this distinct population from the combination, kind of more falls into the TRITON-3 profound kind of monotherapy data with rucaparib and olaparib. In those individuals, I think monotherapy makes sense.
There is a study, an investigator-initiated study led by Dr. Alicia Morgans called the TALENT trial that's looking at the combination of enzalutamide plus talazoparib in a ARPI pretreated population, ARPI-progressing population that'll help shed some light in this space. I think there's also some discussion around what gets classified as a true HRR alteration, and not all HRR genes are created equally, not all directly affect the pathway in the same way. And so while the most robust data is clearly for BRCA1, BRCA2, there's evolving data around, okay, PALB2, ATM, CDK12, CHEK2. And I think there's nuances across the combination studies with regards to the effect size in these non-BRCA HRR subgroups.
Neeraj Agarwal: Well, that's such a comprehensive take. Thank you for taking the time and sharing your wonderful insights.
Rana McKay: Of course, my pleasure. It's a lot of really interesting data, and I think it's great that we have biomarker selected strategies for our patients.