Alicia Morgans: Hi, I'm so excited to be here at APCCC 2022 in Lugano, Switzerland where I have the pleasure of speaking today with Dr. Elena Castro, who is a medical oncologist at the Biomedical Research Institute in Malaga, Spain. As well as Dr. Joaquin Mateo, who is a Geo Medical Oncologist and investigator at Vall d'Hebron in Barcelona, Spain. Thank you both so much for being here with me today.

Joaquin Mateo: Thank you.

Alicia Morgans: Wonderful. So I wanted to speak with you about some innovative data related to genetic testing, PARP inhibitors and all the controversy that's really been sort of lifted up since GUASCO 2022. At that meeting, we saw that in one of the studies, the Propel trial, the combination of abiraterone and olaparib seemed to be associated with radiographic progression-free survival in an all comer population of first line metastatic CRPC patients. And this really, I think, raises a lot of questions because that same population only seemed to respond to the combination of abiraterone and niraparib in a biomarker selected population.

So given all of that, I would love to hear your thoughts on how this data impacts your thoughts about genetic testing, germline, somatic, and what were to make of this data. And we'll give Dr. Castro the first word here. What are your thoughts on this?

Elena Castro: Right. I think as for now, it shouldn't change our clinical practice with regards to the use of PARP inhibitors in CRPC. I think this data is still quite early data and we probably should wait until we have more mature data, including overall survival. And as for now, we should continue to test our patients for alterations in BRC1, BRC2 and HR genes in order to use these PARP inhibitors.

My concern is whether if the Propel study is positive and the combination gets approved, whether we will continue to pursue screening if we don't need it to treat our patients. And germline testing is something that we should continue to do independently of treatment with these PARP inhibitors, because the results of these stats are relevant, not just for therapy, but also for the follow up on the management of the patients. And of course it is important for the relatives who could be at risk of different tumor types.

Alicia Morgans: Well, I could not agree more and think that's such an important part of one of the reasons that we do germline testing and would love to hear your thoughts, especially around next generation sequencing and somatic testing. Because germline testing, I think, has so many, it has broader implications than just the treatment of the patient. What are your thoughts on somatic testing?

Joaquin Mateo: I think that's a very important point. I mean, we have to leave germline testing outside of this discussion, right? Because the primary aim of germline testing is to identify families that may be at higher risk of prostate cancer or other diseases. When it comes to tumor testing, the fact is we know that tumor testing could identify patients who benefit from PARP inhibitor alone. And the rationale behind Propel magnitude and the other studies that many of us are running, is whether by combining with another drug, we can expand this population, the segment of the patient population who benefit a bit more whether it's going to be just a bit more, a lot more, or all of them is what we don't know yet.

And I agree with Elena that probably we need to wait until we have more mature data from these studies. But even if we have positive trials eventually in an all commerce population, that does not mean that is still, we do have the knowledge that there are some patients who benefit more than others from this approach. And I think that from the perspective of the shared decision making with patients and also by pondering risk and benefit, this piece of information will still be important. So I would support that we continue to do genomic testing on tumor tissue up front, even if we have the option of prescribing drugs for patients that may be outside of this biomarker population. Because that will inform us of who are the patients that are more likely to get the biggest benefit. And that's important when deciding therapies for every individual patient.

Alicia Morgans: That's a really great point because especially as we see the survival data, we may see that the magnitude of benefit is something for an all comer population, but it may be a greater benefit for a biomarker selected population and a lesser benefit for an unselected population. And knowing the degree of benefit is going to be so important as we consider the toxicity and the patient's preferences for that intensification.

What are your thoughts in terms of how we might ultimately use the data from these two trials? These were trials that were positive at this point, in terms of radiographic progression free survival. Is this data ready for primetime use in the clinic at this point of time? Whether you're focusing that information on biomarker selected patients or an all comers population, is this something that you would think about using, if you could, in your clinic?

Elena Castro: Yes, for me, what Magnitude clearly says is that the use of PARP inhibitor in patients with alterations in BRC1 and BRC2 shows the greatest benefit with earlier use. So we don't know yet whether the sequence of abiraterone and niraparib in this case will get the same results as the combination. But I think what we learn from Magnitude is that using a PARP inhibitor upfront is definitely better than using abiraterone alone. And then in any case using a PARP inhibitor. And I think for these patients who many of them have very poor outcomes, this is a very important message.

Alicia Morgans: I think that's true. And I think that we'll have to see over time when we're able to use these agents in whom and what that survival data is. Especially with some crossover information or information about subsequent therapies at a minimum. And I wonder in your clinic, Dr. Mateo, are you thinking about this intensification at this point in time? And how are you thinking about that? Assuming you have access and that's something in flux.

Joaquin Mateo: That's a big assumption.

Alicia Morgans: In that's flux, I think, around the world even.

Joaquin Mateo: Yes.

Alicia Morgans: But especially in the context of intensified therapies in the metastatic hormone-sensitive setting, how does that affect what you're doing in MCRPC first line?

Joaquin Mateo: So clearly it will affect because what we are calling CRPC nowadays is not the same entity that we were calling CRPC before. Right? And I totally support some of the things that have been discussed at the APCCC here, on renaming the continuum of the disease, the different stations of the disease.

When it comes to PARP inhibitors in particular, I think that the data we've seen in these trials is quite exciting. But we don't want a drug recommendation approved because it improves PFAs. We use PFAs as a proxy of overall survival benefit when there is an urgency to incorporate a new agent into the care of patients. In this case, it's true that these are two agents that are already available for a biomarker select population in the case of PARP inhibitors and for all commerce in the case of abiraterone. Right?

So I think that in this particular case, it is worse to wait until we have the overall survival data to see if we are really making a difference for patients. Because I think that in the interim, we are not making patients to lose an opportunity because they still can be treated with these drugs per separate.

Alicia Morgans: Yes. That makes sense. And sort of along those lines for a patient who had treatment with ADT and abiraterone, for example. In the metastatic hormone-sensitive setting. Would you think about, again, if you had access adding olaparib or niraparib to that patient at the time of progression?

Elena Castro: Well, at the time of progression, I think at present, we don't have evidence to add the PARP inhibitor on top. But if the patient will have an HR alteration in particularly BRC1 and BRC2, I will switch from my NHT to a PARP inhibitor, that's for sure.

Alicia Morgans: Yeah. Go ahead.

Joaquin Mateo: It's an interesting point. For the BRCA population, clearly you want to give them the PARP inhibitor. Whether you keep the abiraterone or not is a different question that may not only apply to olaparib, but in general, we never remove ADT. Right? With this new generation of treatments, combining ADT and NHTs, will we get to a point that we want to study keeping them forever? I don't know. But we have no data in that space.

Elena Castro: Yeah.

Joaquin Mateo: A different concept is using the combination in non BRCA patients, because we think there is a biological interaction that will result in a synergy. We don't really understand the mechanism behind this interaction, but it seems to be related to the effect between shutting down AR signaling and the olaparib regulation. Clearly using Enz after Abi or Abi after Enz or [inaudible 00:09:21] after Enza, we know that the impact in AR signaling is minimal because there are [inaudible 00:09:26]

So theoretically you are losing their, the rational for that combination. So we should be very careful for interpreting the fact that a few patients on this trials got the drugs also before with we can use them anyway. I would suggest that if we want to study that we need to do a specific trial. But I'm not sure they are the best use of our resources. I think that if we see the point in first line CRPC what we have to do is invest our resources in moving the same combination to the [inaudible 00:09:58] space, where we know that Abi, Enza and [inaudible 00:10:01] make a big difference.

Alicia Morgans: Great answers, and definitely no data. So I appreciate you humoring my question. Final thoughts. What would your message be to the viewers in this rapidly changing space with a lot of gray data? What do you think Dr. Castro?

Elena Castro: Well, with regards to PARP inhibitors and genetic testing and genomic testing, we have to accept that there is some data that is still immature and we will get more evidence in the next months. But as for now, we shouldn't stop testing our patients, the germline, the tumors. And we should still keep considering the use of a PARP inhibitor in patients with this type of alterations.

Alicia Morgans: I agree. Yes. Dr. Mateo.

Joaquin Mateo: I agree. And I think that genomic testing in general brings much more information that the finding of the BRCA mutation that may lead to the treatment indication. Right? We may still don't know how to use this other information in terms of other prognostic biomarkers. But as we learn, and we get more data from the trials that are ongoing, I'm sure that we are going to incorporate genomic testing as one more tool into the individual patient assessment in a more comprehensive manner than just looking at one biomarker, one drug.

Alicia Morgans: Well, thank you both so much for those insights and for your time today, I sincerely appreciate it.

Joaquin Mateo: Thank you.

Elena Castro: My pleasure.