Petros Grivas: Hello, I’m Petros Grivas, I’m a medical oncologist at the University of Washington. I’m an Associate Professor and Clinical Director of the Genitourinary Cancers Program at the University of Washington and Fred Hutchinson Cancer Center. And I’m really honored today to host Dr. Neeraj Agarwal who is a Professor of Medicine at Huntsman Cancer Institute and University of Utah. He’s also the Director of the Genitourinary Cancers Program at the University of Utah. Neeraj, welcome.
Neeraj Agarwal: Thanks for having me, it’s a real pleasure.
Petros Grivas: We’re experiencing really exciting data here at ASCO 2019. We see all this data in the metastatic hormone-sensitive or castration-sensitive metastatic prostate cancer. I would like to ask you from your experience and expertise in this disease, how all this data impacts the management of patients with castration-resistant prostate cancer, especially in the metastatic setting?
Neeraj Agarwal: So that’s an excellent question. We are struggling with … So first of all, great news for the patients. These drugs, when used for castration refractory or castration-resistant prostate cancer patients, they were associated with an improvement of survival in the range of a few months. So we look at, Cougar 1 data, Cougar 2 data pre-chemotherapy, post-chemotherapy, PREVAIL trial with enzalutamide, all showed in overall survival benefit in the range of five to six months. And now, these agents are moving to castration-sensitive metastatic prostate cancer. And we are seeing a multi-fold increase in the overall survival. In the range of almost two years.
So, first of all, this is great news for the patients because they are living longer but the caveat is now we have new challenges. They are living longer and posing new challenges for us, the GU oncologist who are treating patients with prostate cancer. So it’s great that they are being treated with upfront chemotherapy and seeing an overall survival benefit of two years. But now when they are progressing on the first-line, intensified therapies, when they are reaching the stage of castrated resistance, we all know that the drugs, novel androgen access inhibitors, they don’t work as well after chemotherapy. We knew that all along but now it is being reinforced.
Going further in that direction, if a patient receiving abiraterone upfront or enzalutamide upfront, following the ARCHES data or apalutamide upfront, following the TITAN trial data, what options do we have for them? So they are going to live much longer but when they get to the castrate-resistant stage, the options are very limited right now. We know that chemotherapy with docetaxel or abiraterone is not going to be as efficacious in patients who have received this upfront intensified treatment.
So, the challenge is, how to treat these patients. We know we have very few options right now in the form of radium, or cabazitaxel, or docetaxel in those patients but all these therapies that are associated with improved survival in a few months, not beyond that.
So biomarkers, how we move forward, I think a lot of newer novel agents are being explored, being investigated and the field is going to move more towards biomarker selection or patient-driven, tumor driven characters.
Petros Grivas: So, speaking about biomarkers, which I fully agree with you, it’s a very hot and relevant field and hopefully will enable us to select the right patients for that treatment in the future. Which biomarkers come to mind when you think about prostrate cancer, especially castration-resistant disease?
Neeraj Agarwal: I think the most commonly used or interrogated or investigated biomarker-based strategy is PARP inhibitors. So we knew, based on the seminal article published in New England Journal of Medicine, a small trial where patients who had tumors who are harboring DNA repair defect, or homologous recombination defect. Those patients had unusually long progression-free survival, the treatment with olaparib. This was a small trial but it was so impactful, that that single trial alone had led to multiple registration trials which are ongoing right now, interrogating different PARP inhibitors from different pharmaceutical companies in patients with castrate-resistant prostrate cancer. Very soon, we are going to see these trials reporting hopefully positive results and adding these parp inhibitors to the treatment album inventory for these patients.
Now, we saw the results in last ASCO, that when olaparib was added to abiraterone in patients who did not necessarily have mutations harboring DNA repair defects, even those patients responded. The median progression-free survival was significantly longer in patients who received abiraterone with olaparib versus abiraterone alone, regardless of whether they harbored DNA repair defects. And this was something which was really paradigm-shifting. Based on these results, the multiple trials have started in patients, regardless of DNA repair defect.
So yes, we are looking for biomarkers. I think it’s very similar to what we see in other cancer types with immune checkpoint inhibitors, where you have PDL expression. We know they respond better but that doesn’t exclude patients who did not have high PDL expression from responding to this immune checkpoint inhibitors. I think down the line, I’m really hoping, that these PARP inhibitors will show efficacy in patients who have tumors not harboring those DNA repair defects.
Petros Grivas: So speaking about that, I know you have been involved with an interesting study looking at enzoltumide with or without PARP inhibitor and can you inform us about the design of that study and which biomarker you used?
Neeraj Agarwal: Absolutely. So this study, known as TALAPRO-2 study, which is using enzolutamide plus/minus talazoparib, which is another very exciting PARP inhibitor also got approved recently in breast cancer.
Petros Grivas: That’s impressive.
Neeraj Agarwal: So this trial initially started by looking at patients who had tumors harboring DNA repair defects and now this trial has been expanded to a much larger trial and now trial will include patients regardless of DNA repair defects. And we are talking about a trial which has 800 plus patients. So it’s a large, Phase III trial. It’s a multi-national globalist study and I’m really hoping, as one of the study chairs, along with doctor Karim Fizazi, that trial is reported positive. That will hopefully lead to enzolutamide with talazoparib as the new treatment standard for these patients in castrate-resistant prostrate cancer setting.
Petros Grivas: I think clinical trial accrual across the board is so important so I think we should all make an effort to refer patients for clinical trials. That’s how we can create more treatment options. All these trials that you mention are very, very important. Based on your overall experience, what are the take home messages for the audience out there?
Neeraj Agarwal: I think, take-home message for patients with metastatic castrate-resistant prostate cancer, if they have received docetaxel upfront, I think it’s very reasonable to try any of the newer androgen access inhibitors such as abiraterone or enzolutamide. Or any other drugs which may be approved down the line.
If they have received abiraterone or enzolutamide upfront based on two drugs for which we have data right now, I doubt they will see much benefit with either abiraterone or enzolutamide in castrate-resistant prostate cancer setting. So those patients, if they retain performance status, I think docetaxel chemotherapy is the drug of choice for those patients. But beyond that, we have radium-223. But beyond that, I think it is so crucial, it is critical that we promote, we try our best to accrue these patients on the clinical trial so that within the next four or five years, we have a myriad of options which are all targeted therapies based on solid science and scientific evidence.
So, I’m really looking forward to a future, near future, four years down the line. We have multiple drugs, novel drugs targeting novel molecular pathways in patients with castrate-resistant prostate cancer.
Petros Grivas: And also as you mentioned before, have the opportunity to platform to evaluate biomarkers that would hopefully have validation down the road and can help us select the right patients for the treatment in the future.
Neeraj Agarwal: Absolutely. For that accruing on clinical trials is crucial, is critical. Nothing will happen until we have patients who are gracious enough to go on a clinical trial and doctors who are ready to refer or enroll these patients on the clinical trials.
Petros Grivas: And in that note, you have done so much work in clinical trials, so thank you for that. Thank you very much for joining us today. Very insightful input.
Neeraj Agarwal: Thank you very much. It’s a pleasure.