Neeraj Agarwal: Hi, my name is Dr. Neeraj Agarwal. I'm a medical oncologist and a Professor of Medicine at the Huntsman Cancer Institute, University of Utah. Today I'm honored to have Dr. Tanya Dorff, Professor of Medicine in Department of Oncology at the City of Hope. Tanya, thanks for being here.

Tanya Dorff: Good to be here.

Neeraj Agarwal: So we are planning to discuss the evolving landscape of targeted therapy in prostate cancer. Hopefully it is a start. We are going to have many more targetable mutations in prostate cancer. We know about the data on pembrolizumab approval for TMB-high MSI prostate cancer. We are not going to discuss that today, but we'll discuss PARP inhibitor data. So first of all, before we even get into PARP inhibitors, what is your practice as far as NGS testing, germline testing is concerned in your patients with metastatic prostate cancer and high-risk biochemically recurrent prostate cancer?

Tanya Dorff: Yeah, so I think that's a very relevant place to start. When we talk about PARP inhibitors, we know the greatest benefit is in patients who have a mutation or alteration that would predict vulnerability, right, the synthetic lethality. So that requires NGS testing. And in metastatic prostate cancer patients, traditionally we would not use any sort of targeted therapy until castration resistance, but that's probably going to change with some of the newer data. And I think that plus some of the other trials that are reporting out, like CAPItello-281, just provide a really compelling rationale to do that NGS testing earlier so we can learn more about our individual's prostate cancer, how it will behave, what it might respond to, even in the hormone-naive setting before they've had their first-line therapy.

So germline testing has always been recommended for any advanced prostate cancer, but I think what's changing is that there's more actionability to doing somatic testing in the context of a newly diagnosed metastatic hormone-sensitive and maybe even in the high-risk biochemically recurrent or high-risk locally advanced setting.

Neeraj Agarwal: Absolutely. And also, many times these patients, they do so well in metastatic hormone-sensitive prostate cancer for years that by the time they are developing mCRPC, the original prostate tissue, the primary tissue is not eligible, no longer eligible for testing. And we saw that problem with the PROfound trial when 30% of patients were not eligible for the trial just because they did not have sufficient quantity or quality of tissue left.

So I agree with you. I'm increasingly ordering NGS testing. Pretty much all my patients are offered NGS testing of the tumor in hormone-sensitive metastatic prostate cancer to look for those targetable mutations down the line, but also to look for clinical trials, and with hopefully AMPLITUDE trial being positive, we'll have options for these patients, and the CAPItello trial.

Tanya Dorff: It's a great point about the tissue. I mean, I will raise the fact that you can use ctDNA to qualify a patient for a PARP inhibitor. I just want that to be out there. That was allowed on some of the trials. However, we know that ctDNA can be tricky in prostate cancer and if there's not enough disease volume, you might get a false negative, so tissue testing really is preferred. And as we've said, there's just more and more compelling reason to just do it early.

Neeraj Agarwal: Yeah, and ctDNA is a great adjunct. If tissue is not available or not there, biopsy is not possible, I rely on ctDNA a lot. I agree with you. So let's talk about PARP inhibitors. I know monotherapy data had been presented over the last almost six years now. Hard to believe PROfound trial was presented in 2019, and Olaparib has been approved for six years now. What is your practice from the monotherapy perspective? Pre-chemo, post-chemo? Where do you like to use them in genomically selected eligible patients?

Tanya Dorff: Well, so specifically for patients with a BRCA2 alteration, the TRITON3 study showed us that actually the PARP inhibitor yielded better outcomes than docetaxel. That's really the only study that compared head-to-head. The other ones were all really comparing against AR pathway inhibitor switch, which we know has limited efficacy. So those data were very compelling that this mutation is really a strong predictor of benefit from this class of drugs. And so in those patients, I certainly try to use the PARP inhibitor as early as possible.

Some of the patients with the other mutations, I think the data become a little less clear in part because there just aren't as many of those patients and the signal seems to be mixed between the monotherapy and the combination trials. So I don't know how you feel about the evolution of the treatment of some of these mutations like CDK12 and CHEK2 and PALB2 on the basis of both the monotherapy and then the combination studies.

Neeraj Agarwal: Yeah, that's a great point, Tanya. I think there is definitely difference in the activity of PARP when used as monotherapy versus when used as combination therapy with ARPI. Definitely the magnitude of benefit seems to be higher when combined with ARPI, and that can be based on a lot of preclinical rationale. Starting in 2012, Dr. Karen Knudsen presented the data on crosstalk between AR and DNA repair pathway and so on.

And then we did see in the, for example, Enzalutamide plus Talazoparib trial, there was definitely activity in patients beyond BRCA2, so patients with BRCA1 mutation, CDK12 mutation, PALB2 mutations definitely seem to benefit. Significant benefit is present in these patients. If you look at the forest plots hazard ratios for BFS and OS, and I think there is definitely a different type of signal, efficacy signal present when combined with AR inhibitors.

Tanya Dorff: Now, those trials were largely in the absence of prior docetaxel as opposed to the monotherapy trials, which had a lot of prior docetaxel. Would you use a combination AR pathway inhibitor and PARP inhibitor post-docetaxel in select patients? Would the mutation dictate that?

Neeraj Agarwal: Again, docetaxel, if you look at docetaxel, which was approved in 2004 when there were no ARPIs existing at the time, and there are no prospective data favoring docetaxel, comparing docetaxel with ARPI ever. We have CARD trial data in the third line setting after ARPI and docetaxel and in that trial, patients selected had to have poor response to the first ARPI, so relatively ARPI-resistant population who are randomized to cabazitaxel versus alternate ARPI.

But coming to docetaxel, we don't have any prospective data, but definitely it's a viable treatment. It's a treatment I use all the time and I will not preclude anything for all patients. This is very customized decision-making for individual patients based on their performance status, disease characteristics, their preferences for oral versus IV therapies and so on.

So one thing is, which is often highlighted for all these trials which are done in mCRPC setting, that their population did not receive ARPI or docetaxel to any substantial extent. For example, in TALAPRO-2 study, only 21% of patients had received therapy intensification in metastatic hormone sensitive setting. And can we apply the data in the hormone in a CRPC setting? That's a question often comes up, but if you look at many other trials which are reported including docetaxel, we don't have any data how efficacious they will be after prior ARPI.

So given that, I think I keep it very simple. I first decide whether I'm going to use enzalutamide or an ARPI or not. And these are those patients like Dr. David Morris brought up during the 2025 USPCC meeting today, that patients who are progressing slowly on abiraterone, they have not really met the radiographic progression-free criteria based on COU-AA-302 trial and they want to switch the treatment, they felt comfortable moving to enzalutamide. Also, there are at least seven trials going on to my knowledge which are using limited duration ARPI in the pre-mCRPC setting. So all those patients, when they develop mCRPC, many of them may be ARPI exposed, but not ARPI progressed. So I think the field is emerging and we will see how it goes, but if I'm using enzalutamide and if patients have HRR mutations, I definitely offer them an option of getting talazoparib.

Tanya Dorff: I think you raised a great point. I mean, the data are imperfect and we have to have shared informed decision making, what are the risks and benefits and making sure our patients get as much effective therapy earlier. And speaking to earlier, it's exciting that PARP inhibitors might be tested even earlier in localized or locally advanced sort of disease states.

Neeraj Agarwal: Yeah, so there are two trials going on in metastatic hormone sensitive setting. So AMPLITUDE trial was just presented. Hopefully that will lead to the approval of abiraterone plus niraparib for patients with mHCPC with eligible mutations, which were included in the trial. And then TALAPRO-3 and EVoPAR-Prostate01 trial are testing the efficacy of ARPI plus talazoparib and ARPI plus saruparib respectively.

Now, EVoPAR-Prostate02 trial has moved even further downstream, or upstream if you will. Patients with locally advanced prostate cancer or high risk biochemical recurrent disease, if they have BRCA2 and BRCA1 mutation, they are being randomized to ADT plus ARPI plus minus saruparib. So I think this field will continue to evolve and we will hopefully see many more options for our patients. And ultimately, key challenge will be how to select patients. So my question is how are you going to select patients if you have T-cell engager, CAR T cells, which you have been pioneering and all these other therapies, radioligand therapy, signaling inhibitors, biomarker based therapies, how do you see the future evolving?

Tanya Dorff: Yeah, I think it will be challenging, but it's a good challenge to have, especially for our patients to have multiple options. It does get more confusing, but this is where the science is so important to be embedded together with the clinical research, because if we just test all prostate cancer patients with this approach and that approach, then it will be impossible to sort out what would be best for an individual patient.

So it's the embedded science that Prostate Cancer Foundation supports so much of, and a lot of investigators that you and I work with are doing at their institutions that is going to give us the tools to say, "For you, for this patient, out of these various approaches, here's the one that will be likely most successful," and I think also we'll have to look at toxicity profiles and are there late toxicities? Are there irreversible toxicities, cost, insurance access? There will always be other factors that are discussed as part of the decision-making, but certainly it's exciting that more effective therapies are being developed and moving earlier.

Neeraj Agarwal: As you said, it's a good problem to have, to have so many therapies and hopefully artificial intelligence will help us in therapy selection. Well, thank you, Tanya, for being here. It was so nice to discuss these options with you.

Tanya Dorff: Yeah, thank you.