Andrew Armstrong: Thank you, Neeraj, and congratulations on your new appointment coming up, so.
Neeraj Agarwal: Yes, thank you. So please tell us about your take on TALAPRO-3 trial. It was a phase-three trial, just presented and published. And we'd love to have your take.
Andrew Armstrong: Well, first, congratulations on leading such a great series of TALAPRO studies, and it builds on the success that you and I have both had with PARP and AR inhibitors in the androgen pathway modulator resistant setting. So these new doublets, we both established as important in delaying progression and improving survival, particularly in the BRCA patients, but also in the homologous repair population. But we have to follow the lead of where the ARPIs are being most utilized in the United States and globally right now, which is in the androgen pathway modulator sensitive and naive population. So the vast majority of patients, probably 90% deserve an ARPI in this early setting, and that's because survival is improved, progression is delayed. And that synergy with a PARP inhibitor is probably best observed when the cancer's most sensitive to an AR inhibitor. And so TALAPRO-3 was that kind of question.
It took an ARCHES type backbone, which was ADT Enza, and attempted to build on that with Talazoparib. And Talazoparib's a very potent PARP1/2 inhibitor, PARP trapper, already effective at improving survival, already FDA approved, but now moving into this early setting. And congratulations on a positive result in New England Journal paper using the Prostate Cancer Working Group 4 language. Successful study in all of its endpoints, particularly as I would just like to point out, not just in the BRCA2 population.
Neeraj Agarwal: Yeah. And we want to make it conversational because I'm really trying to get your viewpoints on this.
Andrew Armstrong: Yes.
Neeraj Agarwal: So I'll summarize the study results. About 600 patients with newly diagnosed metastatic prostate cancer now called as metastatic androgen pathway modulation sensitive prostate cancer because never liked the word castration-
Andrew Armstrong: No.
Neeraj Agarwal: For our patients to be used in the clinic. So I'm so glad we have this new terminology. And they had to have HRR gene mutations.
Andrew Armstrong: Yes.
Neeraj Agarwal: So 35% of these patients had BRCA2, BRCA1 mutations, BRCA2 being the most common. ATM was 30%. CDK12, 18%. So all those usual suspects were there. And these patients were randomized to ADT plus Enzalutamide, the ARCHES backbone, as you said, plus Talazoparib versus placebo. Radiographic progression-free survival was the primary endpoint, which was met about 50% reduction in risk of-
Andrew Armstrong: Yes.
Neeraj Agarwal: Progression or death.
Andrew Armstrong: Great results.
Neeraj Agarwal: 52% to be precise. And other secondary endpoints like PSA progression, the time to chemotherapy, subsequent therapy, all were about 50% reduction in risk of all of these endpoints and overall survival data are immature right now.
Andrew Armstrong: Yes.
Neeraj Agarwal: So that's a overall snapshot. We saw a lot of anemia, Grade 3 anemia in 51% of patients. Happens early on after three months. Median onset is three months. You decrease the dose of medicine, Talazoparib, and it tapers off, so-
Andrew Armstrong: Absolutely.
Neeraj Agarwal: Which was nice. Only 5% of patients actually discontinued Talazoparib because of Grade 3 anemia. So Andy, coming back to you about based on these results, where do you see these results in the context of everything else which is going on?
Andrew Armstrong: Well, first off, it emphasizes the importance of early genetic testing. We all have international guidelines that say germline testing for all patients basically with prostate cancer right now, at least with metastatic and high-risk disease. But somatic testing has largely, until this year, been reserved for men with APMR prostate cancer because that's where the PARP inhibitors, Pembrolizumab and precision medicine has been applied. And now with AMPLITUDE and TALAPRO, it's very clear we need to know that information upfront to better the outcomes of our patients. And so a somatic test should be ordered, maybe at your first or second encounter with a patient with metastatic disease. It takes a few weeks sometimes to get those results back. If it's a Foundation or Caris or Tempus or institutional test, it may take a little while to mobilize the tissue. A liquid biopsy is acceptable. That was used in TALAPRO-3, but ideally before you've started the patient on systemic therapy, because that cell-free DNA can resolve very quickly and you may get an uninformative result. So number one is test your patient. Then you can make that best-
Neeraj Agarwal: And just a quick question on that. Any PSA level you follow before you decide not to order liquid, like ctDNA testing in your clinic?
Andrew Armstrong: You mean post-treatment?
Neeraj Agarwal: Let's say a patient came to me, has already started ADT injection, and now PSA is rapidly going down.
Andrew Armstrong: Yeah.
Neeraj Agarwal: So what is the cutoff, a rough cutoff for our colleagues out there in the community after which they should not be ordering ctDNA testing?
Andrew Armstrong: It's a great question. My preference is once you've got a patient who's already on hormonal therapy is to order tumor testing from the prostate biopsy. Most of these patients have a very fresh biopsy because they've had de novo metastatic disease. If they have recurrent disease, they have tissue from their prostatectomy. So I think that's what my default would be. Now, ctDNA goes away within about two to three weeks. So you don't have very long to get that ctDNA. So if it's within a week, I think it's reasonable. But if you get an uninformative result, meaning there's no ctDNA, doesn't mean the patient's negative. So you can still go and order the tumor test.
Neeraj Agarwal: Yeah.
Andrew Armstrong: Yeah.
Neeraj Agarwal: Thank you. So coming back to your take on the overall landscape and how do we position TALAPRO-3?
Andrew Armstrong: So we have many triplets now. TALAPRO-3 did not require or allow prior docetaxel. So that is a conventional triplet that we might use in high volume patients, particularly those with liver metastases, those who have the greatest unmet need. For those with homologous repair deficiencies, I think starting at the top, a patient with a BRCA2 mutation, there's a phenomenal benefit from a PARP inhibitor, particularly talazoparib. We have ongoing studies, the EvoPAR study looking at Saruparib. We have the AMPLITUDE study. These are the patients most exquisitely sensitive to that synthetic lethal approach where there's a homologous repair defect. You block PARP, the tumor dies, and you see a much greater effect both on PSA outcomes, objective responses, delays, progression, and survival.
Surprising to me in TALAPRO-3, we're now starting to see efficacy in ATM, and CDK12, and even BRCA1 patients where sometimes these are subclonal or they're more heterogeneous. They're not homozygous deletions like we commonly see in BRCA2. And so maybe there's a greater AR PARP inhibitor sensitivity in these patient populations early on when you use it rather than much less efficacy when you use them later. So your best weapon is your first weapon upfront.
Neeraj Agarwal: Yeah. And surprisingly, CDK12 has a ratio for rPFS, 0.27.
Andrew Armstrong: Incredible.
Neeraj Agarwal: For ATM is 0.48. So better than BRCA1 actually.
Andrew Armstrong: Yes.
Neeraj Agarwal: So it was definitely different from other combinations. And I think it has to do with, as you said, the combination of a potent ARPI, Enzalutamide. I personally think Enzalutamide was one of the most effective ARPIs-
Andrew Armstrong: Yep.
Neeraj Agarwal: And which you got into our clinic for metastatic hormone-sensitive setting or APMS setting.
Andrew Armstrong: Yes.
Neeraj Agarwal: And Talazoparib. So I think it's a combination of these two, which is unique in the sense from the synergy perspective, mechanistically speaking, likely that's why we are seeing those results.
Andrew Armstrong: Yeah. There's certainly some interactive biology where PARP may regulate AR and AR may regulate DNA repair independently of each other. And so I think there is some likely synergy with that upfront use.
Neeraj Agarwal: Yeah. So testing is the key, looks like.
Andrew Armstrong: Testing is the key.
Neeraj Agarwal: So anytime we see a newly diagnosed patient with metastatic prostate cancer or metastatic APMS disease, we have to order somatic testing and germline testing.
Andrew Armstrong: I think in the best interest of our patients, we're going to be ordering PSMA PET imaging, PTEN immunohistochemistry, next gen sequencing. I think that will be part of the quality care metrics we'll be judged on.
Neeraj Agarwal: Precision therapy has started in prostate cancer.
Andrew Armstrong: Yes.
Neeraj Agarwal: Yeah. Thank you very much.
Andrew Armstrong: Great discussion, Neeraj. Thank you. Congratulations.