Alicia Morgans: Well, thank you so much for having me.
Neeraj Agarwal: So we saw so many trials reporting positive, great news for our patients in metastatic hormone-sensitive prostate cancer, now known as metastatic androgen pathway modulation sensitive prostate cancer. And one of them is the CAPItello-281 trial with capivasertib, AKT inhibitor. So we'd love to have your insights, your perspective on the trial design, results, and what are the implications for our patients?
Alicia Morgans: Absolutely. So I think importantly, the first thing we should share and make sure is really clear is that we now have an FDA approval for patients to receive capivasertib and abiraterone with prednisone in this APMN or S setting, metastatic hormone-sensitive prostate cancer as its old name. And I think that's really very exciting, as you said. Importantly, this study demonstrated that the combination of capivasertib and abiraterone improve radiographic progression-free survival against that control arm of abiraterone and ADT alone, which is a highly active control arm and really, really exciting. But also importantly, this specifically identified a patient population that makes up about 25% of that APMNRS population who have PTEN deficiency identified by IHC as a 90% or more loss. And with all of the incremental increases in PTEN loss for these patients, we see there's an even bigger benefit to the addition of capivacertib to an abiraterone backbone.
Also, so importantly, this study demonstrated to me that those patients with this degree of PTEN loss have quite an aggressive disease phenotype. And I don't know that we've really talked about this as a particular subgroup within that hormone sensitive or APMN or S subtype of patients with prostate cancer. So it helps us even understand the heterogeneity of disease more and also identifies this high-risk subgroup. So all of that's really important. But what's so important as we now have this approval and are now thinking about integrating this into our workflows is thinking about how do we identify the patients and then how do we keep them safe and monitor them appropriately as we treat them?
Neeraj Agarwal: Absolutely. Great point. First of all, the trial required 90% loss of PTEN by immunohistochemistry. And as you pointed out, the radiographic progression-free survival was literally half of what we usually see with ADT plus ARPI backbone. It was 25 months. And with the increasing loss of PTEN to 99% or 100%, the radiographic progression-free survival was even lower at 22%. So I think it's a very different subset of patients who really need something else beyond ADT plus ARPI.
And frankly, I have not seen any chemotherapy data showing benefits. So the notion that docetaxel may work here is not really based on prospective control trials. And in that context, to have a drug which is effective, we'll come to that in a moment, which improves outcomes, is really a welcome news for us. So that is a nice segue to the efficacy results of this trial. So what is your take on the efficacy data?
Alicia Morgans: Well, I absolutely think that this is something that, again, changes the trajectory of disease, prolongs radiographic progression-free survival, and is something that we can incorporate into our algorithms for this biomarker selected population. And in my clinic, we are using IHC to do this identification of patients, and that's how it was done in the CAPItello-281 trial. And I've been able to talk with my pathology colleagues about simply testing for patients who have metastatic disease for PTEN loss.
Unlike in the study, at least in my center, our pathologists have not been able to say to a degree of precision that this is 99% loss or 95% loss, but they can absolutely tell us or so they assure me whether it's greater than 90%, and they can also say whether there's 100% loss. There are assays for organizations that do not have a pathologist who's able to do this assay, which is a VENTANA assay for IHC.
And I think that's a perfectly great way to do it as well, the send out test to try to get this identification. But it should be pretty rapid to turn around if it's an IHC test within your own institution and actually pretty quick on the send out as well, from what I understand. So identifying the patients, thankfully, is not going to be as big of a barrier as we might've thought initially.
Neeraj Agarwal: Absolutely. So coming to the PTEN loss and implications, before we get to the radiographic progression-free survival benefit, which was almost a year better in a higher level of PTEN loss patients, 22 months to about 32 months, which is quite remarkable, I also found one of the findings very interesting. About one third of these patients developed radiographic progression without meeting the criteria for PSA progression. So what is your take on this?
Alicia Morgans: I think this really goes to the point that this is a unique patient population with a disease biology that does not necessarily follow something that's clearly only driven by androgen receptor pathway signaling. And that this approach by integrating this PTEN deficiency AKT inhibition sort of approach is something that can be really uniquely helpful for this patient population. And it isn't surprising necessarily that we see them having radiographic progression without PSA progression because of the way PSA is so tightly tied to that androgen receptor pathway. So it, again, reiterates that this is a unique population that needs a unique mechanism of action to really drive that benefit home.
Neeraj Agarwal: And not only I'm going to seek capivasertab in this patient population, but I'm also actually going to change my practice of how frequently I do scans in these patients. And otherwise, patients with APMS, I don't necessarily do scans every three months. If they're responding very well, doing really well, maybe once a year, twice a year. But for PTEN loss patients, I think I'm going to change my practice to do conventional scans or PSMA PET scans, CT scans, bone scans every three months, whatever is allowed by their payers, because many of these patients are going to be developing radiographic progression without PSF progression.
Alicia Morgans: I could not agree more. I think that's a great point to make. And I think that sometimes we'll have to make sure that we adapt that imaging strategy to be something that we can monitor over time, to your point about payers, and also to make sure that we're capturing disease in the areas that it is. I have a patient with PTEN loss who is difficult to capture bone lesions on bone scan or on CT really reliably, but I've been able to use MRI to show progression in that setting. And I think that that's something that we're going to also have to think about doing. What is the best strategy to capture progression or response in this particular patient, recognizing that it can be a little bit more challenging sometimes?
Neeraj Agarwal: Having discussed the implications of these trial results on testing, immunohistochemistry looks like it's going to be a standard of care for patients with newly diagnosed APMS prostate cancer, and then how we follow them with imaging studies other than using capivasertab for those patients. Any comment on the side effects, management of capivasertab?
Alicia Morgans: Sure. I think this is something that I've been really eager to work with my team to develop a strategy around because the proactive management of side effects here is going to be important both for safety and also to ensure that patients are able to stay on treatment. I've been able to work with colleagues who treat breast cancer in my center to understand what they're doing, which has been very helpful as well. So thinking about getting patients home glucose monitors so that they can do their weekly checks, usually on day three or four for the first number of weeks as they start treatment, that then becomes a little bit less common. But that's been something that the breast cancer group has been very able to do, even in patients who do not have diabetes by coding that as using a blood glucose monitoring system for patients for drug monitoring. That's how that's been coded and it's been successful.
I think we've also talked about getting hemoglobin A1Cs as well as that fasting blood sugar at baseline to ensure that patients are safe to start on treatment and to work with primary care or endocrinology to make sure, again, that patients have that controlled blood sugar below threshold before they're actually initiated on therapy. And we do have some time based on the parameters within the trial to get that all sorted out before we start the cabevasirtib. The other thing that I think has been really helpful from their perspective has been to talk to patients about prophylactically starting a non-sedating antihistamine agent to prevent rash and to monitor them in terms of any diarrhea development, using things like Imodium proactively to help them ensure that they're able to take their medication and not have diarrhea that becomes more troublesome.
And the proactive management, the strategies of engaging and arming patients to be ready for what they may face, and then to have, again, clear communication with our team should they develop these complications, I think is going to be and is already and will continue to be a really successful strategy to keep them safe and well.
Neeraj Agarwal: Those are wonderful points. And to allow our patients to survive and to get benefit from capivasertab in this very aggressive disease setting, I think it's going to be very important to manage the side effects and to learn from our breast cancer colleagues who have been using Capivasertib for quite a while now.
Alicia Morgans: Absolutely. I could not agree more.
Neeraj Agarwal: Well, thank you, Alicia, for sharing your perspective on the implications of Capital 281 trial, on testing, on monitoring, on treatment, and managing side effects in our patients.
Alicia Morgans: Thank you so much, Neeraj.