TITAN, TALAPRO-2 And Ongoing Clinical Trials for Prostate Cancer - Neeraj Agarwal

August 18, 2019

Petros Grivas invites Neeraj Agarwal to discuss the TITAN trial which reported the first interim analysis at ASCO 2019.  The TITAN trial is a "Study of Apalutamide Plus Androgen Deprivation Therapy (ADT) Versus ADT in Participants With metastatic hormone-sensitive prostate cancer (mHSPC).  A total of 525 patients were assigned to receive apalutamide plus ADT and 527 to receive placebo plus ADT. The median age was 68 years. A total of 16.4% of the patients had undergone prostatectomy or received radiotherapy for localized disease, and 10.7% had received previous docetaxel therapy; 62.7% had high-volume disease, and 37.3% had low-volume disease. At the first interim analysis, with a median of 22.7 months of follow-up, the percentage of patients with radiographic progression-free survival at 24 months was 68.2% in the apalutamide group and 47.5% in the placebo group (hazard ratio for radiographic progression or death, 0.48; 95% confidence interval [CI], 0.39 to 0.60; P<0.001). Overall survival at 24 months was also greater with apalutamide than with placebo (82.4% in the apalutamide group vs. 73.5% in the placebo group; hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005). 
In this trial involving patients with metastatic, castration-sensitive prostate cancer, overall survival, and radiographic progression-free survival were significantly longer with the addition of apalutamide to ADT than with placebo plus ADT, and the side-effect profile did not differ substantially between the two groups.  Dr. Agarwal says apalutamide is a safe and tolerable drug for men being treated for prostate cancer.  They continue to discuss ongoing trials that were discussed at ASCO in mCRPC including the TALAPRO-2 trial.  The key challenge and opportunity will be patient selection.


NNeeraj Agarwal, MD, Professor in the Division of Oncology, Department of Medicine, at the Huntsman Cancer Institute (HCI) at the University of Utah School of Medicine. He is the Huntsman Cancer Institute (HCI) Presidential Endowed Chair of Cancer Research, and the Director of the Genitourinary Oncology Program, Dr. Agarwal also serves as the physician-scientist and senior director of clinical research innovation at HCI, Salt Lake City, Utah

Petros Grivas, MD, Ph.D., Clinical Director, Genitourinary Cancers Program, University of Washington Medicine Associate Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine

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Petros Grivas: Hello. I'm Petros Grivas. I'm a medical oncologist at the Seattle Cancer Care Alliance and Associate Professor of Medicine in University of Boston and Fred Hutchinson Cancer Research Center. I'm thrilled today to host Dr. Neeraj Agarwal, who is a full Professor of Medicine at the Huntsman Cancer Institute, University of Utah and he has a leading role in multiple clinical trials in genitourinary cancers. Dr. Agarwal, welcome.

Neeraj Agarwal: Thanks for having me. It's always a pleasure.

Petros Grivas: It's fantastic to be here at ASCO 2019 and I would like to personally congratulate you on a really huge accomplishment. You are one of the leaders in a significant clinical trial called the TITAN. That was presented yesterday by Dr. Chi at ASCO 2019 and these results of the trial were presented and published in the New England Journal of Medicine, so huge accomplishment. Congratulations. Being in this leadership role, I would like to pick your brain and tell us a little bit more about the TITAN trial and their results, their methodology, and also put it in context of the landscape of metastatic hormone sensitive prostate cancer.

Neeraj Agarwal: Thanks for your words about TITAN. We are very happy to see the results of the TITAN study. As you know, Titan was a large phase three randomized clinical trial of more than 1000 patients who were, who had a diagnosis of hormone sensitive or castration sensitive metastatic prostate cancer. And these patients were randomized to standard of care androgen deprivation therapy versus standard of care plus the new potent direct androgen receptor inhibitor, apalutamide. And all what we saw was really remarkable.

At the first interim analysis, both primary endpoints, number one, radiographic progression free survival, and number two overall survival. Both primary endpoints were met at the time of first interim analysis. So, this was really striking.

Petros Grivas: Very early on.

Neeraj Agarwal: Very early on. And, and that led to basically unblinding of the trial and crossover of the patients to patients who were getting placebo. They were allowed to cross over to apalutamide as suggested by the independent data safety monitoring committee. So this is a great news for our patients. We have a new drug which is an oral pill, doesn't require steroids in the form of apalutamide for our patients. So yes, indeed. Indeed it is great news.

Petros Grivas: Do you see the toxicity profile of apalutamide different to that of abiraterone or enzalutamide in that context? Is it relevant or how do you envision that toxicity profile to play a role in the decision making process down the road if the drug becomes approved?

Neeraj Agarwal: Yes. So the first of all, the question is how apalutamide is going to impact the current standard which are already approved. So we know docetaxel chemotherapy is one of the choices in this setting. Another drug, other combination is abiraterone with prednisone. I don't think I've had, if I recall, if I think about last hundred patients of mine with this diagnosis, I cannot think about a single patient who was enthusiastic about receiving chemotherapy. So we all know about short term and long-term side effects of chemotherapy. So in my view, this is a pretty straightforward decision that we can avoid chemotherapy by using apalutamide. Now let's come to abiraterone with prednisone. Abiraterone is an oral pill or rather pills. But we also know that it required concomitant steroids and this is not a castrate resistant prostate cancer setting where abiraterone is going to be used for less than one year. This is hormone sensitive setting where we are talking about treating someone, newly diagnosed patient for potentially two to three years. It can go into years. So, what really bothers me is the concomitant use of steroids, which is required for patients who are being treated with abiraterone for years and its own set of complications such as osteoporosis and metabolic, you know, all the metabolic symptoms including glucose, you know, intolerance and so on.

So, I think if I compare apalutamide with the current standards, in my view it's a very straightforward decision that we can avoid chemotherapy, we can avoid steroids and apalutamide is a great choice.

Petros Grivas: And it's interesting because we don't have any comparison head to head directly between those agents. And so we, it's always very hard and cumbersome to extrapolate data and compare across trials. But I think your perspective is always very useful. We're going actually to move on to castration-resistant disease in a second, but before I do that I would like to ask you about the other data we're seeing at ASCO, the ENZAMET trial, which is part of the plenary session. Very important study by Dr. Sweeney and colleagues. How does the study play a role in this context of the landscape that is evolving in the metastatic castration stage prostate cancer?

Neeraj Agarwal: Right, so again, great question. Before we talk about ENZAMET, we know the ARCHES trial which was presented in a GU ASCO a few months ago showed that ARCHES met the primary endpoint of radiographic progression free survival. Overall survival had not been met at the time of first interim analysis in the ARCHES trial. So we are looking forward to see how it is going to pan out. But ENZAMET is a plenary session abstract and it is assumed that if it is a plenary session abstract, it has met the overall survival endpoint in my view. And given that, I think this is another great choice for our patients. Enzalutamide is a drug which is already being used and I think experience with enzalutamide is definitely there among urologists, among oncologists. What is really interesting in my mind is that ARCHES trial did not lead the overall survival endpoint at the time of first interim analysis and TITAN trial met the primary endpoint of overall survival as well as radiographic progression free survival. So is there a difference in these two drugs? As you said, these drugs have not been compared with each other in a randomized controlled setting. So it's hard to tell if one is superior over the other, but I think as for now, based on the data we have, I think these are both very good options.

Petros Grivas: It's always good to have options for patients. It's what we call the embarrassment of riches. What is happening right now in metastatic castration sensitive prostate cancer. As you mentioned, patients have the options of getting ADT, androgen deprivation therapy, abiraterone with prednisone based on the LATITUDE and STAMPEDE trials or docetaxel based on the STAMPEDE on the CHAARTED trials. And now we have more options with enzalutamide or apalutamide based on the ENZAMET, ARCHES and the TITAN trial that we are part of the leadership.

Neeraj Agarwal: So I just want to make one quick point. Having participated and enrolled patients and treated patients with apalutamide and I think people will have very similar experience when we treat and use apalutamide for patients for non-metastatic CRPC. The tolerability is extremely good. I think the level of fatigue we are seeing with apalutamide is not remarkable at all, so patients tolerate the drug very well. It was also shown in the paper quality of life, patient reported outcome paper of the SPARTAN trial where they showed that apalutamide with the use of apalutamide, patients reported outcomes were actually even better than what they were seeing with the control arm. So, we are going to look at the patient reported outcome data from the TITAN trial. But based on what I've experienced so far, I in my view, apalutamide is a highly well-tolerated drug and it's going to be one of the leading options for our patients who have newly diagnosed or hormone-sensitive metastatic prostate cancer.

Petros Grivas: Interesting. Very interesting. And you are also leading another large trial, the SWOG trial evaluating another anti-androgen agent, actually androgen biosynthesis inhibitor TAK-700 so that's another trial that is coming down the line and you have been the PI of the trial, right?

Neeraj Agarwal: Yes. So SWOG 1216 is androgen deprivation therapy with or without TAK-700, so just to put a, trying to bring memories back. TAK-700 or orteronel did not succeed in castrate-resistant prostate cancer setting, which I partly attribute to the fact that abiraterone got approved in the middle of the trial. Having said that, using deeper androgen blockade strategy in hormone-sensitive setting has proven to be very successful with multiple drugs getting approved in this setting. So I'm really hoping that SWOG 1216 trial is positive. We are really hoping that results will be available by end of this year and we'll be talking about the trial next ASCO with positive results. I think the advantage of this trial, if the trial is positive, I think that novelty about this trial will be that TAK-700 is a androgen synthetic blocker and doesn't require concomitant steroids.

Petros Grivas: Interesting.

Neeraj Agarwal: So I think as a new it will be a new class of drug and new option for our patients and time will tell if the trial is positive or not.

Petros Grivas: We look forward for the results. Another contribution to the field. Dr Agarwal. Before we conclude, I would like to pick your brain about castration resistant prostate cancer and specifically the field of PARP inhibitors and you have been also part of important trials like the TALAPRO trial and we also saw yesterday at ASCO, data from the TOPARP-B trial from Dr. Mateo and colleagues, so you can synthesize a little bit the data with PARP inhibitors in prostate cancer and put it in context for the audience and tell us a little bit about patient selection. Does it matter which assays does the sequencing depth or coverage matter which mutations and or should we go unselected patients especially with combination strategies like in your study?

Neeraj Agarwal: Yeah, so these are many questions and I'll try to summarize them in two minutes. So first of all, does it really matter? Patient selection matters and I think the biggest challenge we have is how to select those patients. So we know the patients with BRCA2 and BRCA1 are more canonical mutations in DNA repair pathway such as ATM. They're likely going to respond, but then we start looking at other minor non-canonical genes which are, which belonged to non-canonical pathway or not the traditional pathways and we don't see the responses in those patients similar to what we are seeing with patients who are harboring BRCA2 mutations or ATM or BRCA1. It only tells me, it doesn't tell me that other patients are not going to respond. It only tells me that we do not know how to select the patients. That's the number one challenge we have.

Every year the gene panel keep getting widened or keep getting modified depending upon what kind of mutations we are talking about. Those genes which were historically considered to be a part of DNA repair pathway, they are no longer considered part of DNA repair pathways. So I think the whole field is very challenging. So the next step is to think about do we really need to select patients? And in my view, probably not, especially with potent PARP inhibitors like talazoparib. Talazoparib is a PARP inhibitor, but it is a unique drug in the sense that in addition to inhibiting the PARP enzyme, it also traps PARP on the DNA. So, this drug talazoparib may not require concomitant deficiency of DNA repair defects. Patients who have intact DNA repair pathway in their tumors or germline, they may still respond to talazoparib because of this unique mechanism of action with the big caveat that we have not shown that yet, the trial is still going on.

But one other interesting fact or report we just came up like in last year, in last one year, is that when we use these androgen blockade, when we utilize androgen blockade against prostate cancer cells, they tend to rely more on PARP enzyme regardless of underlying DNA repair defect.

Petros Grivas: Interesting.

Neeraj Agarwal: So, this data was very telling that when you're using enzalutamide, you'll see up regulation of PARP. So, if you are using enzalutamide, if you use PARP inhibitor it may make the cell very susceptible to kill by enzalutamide regardless of underlying DNA repair defect. And that's the concept we are testing right now in a phase three randomized controlled trial which is already open in 27 countries. It is going to accrue more than 800 patients and patients are going to be randomized to enzalutamide versus enzalutamide with talazoparib.

Petros Grivas: Interesting.

Neeraj Agarwal: So in this ASCO we are, we just presented the safety part of this, this combination is very safe and now we are going to test the efficacy in this large global trial.

Petros Grivas: Very interesting perspective. And you know, back to your points, you know there are different mutations and alterations and we don't know exactly how they respond, especially in a single agent PARP inhibition context and ATM. Many patients may not respond, very few may respond, but then you have combination strategies. I think maybe a different question and whether the relative significance of these alterations, you know, are the same or different if you have a single agent PARP inhibitor versus combination. And there are many examples of -

Neeraj Agarwal: Exactly. So in my view if you use PARP inhibitors in combination, you may not require underlying DNA repair defect in the cancer cells.
Petros Grivas: Interesting. And you are testing this hypothesis in the TALAPRO-2 trial, correct?

Neeraj Agarwal: Yes. TALAPRO-2 phase three randomized controlled trial.

Petros Grivas: Interesting. I think we're learning more and more. All these trials, TOPARP-A, TOPARP-B, TRITON trials, many other using PARP inhibitors I think are very insightful and we're going to get more and more data and our job is to make some sense out of this data flood as I call it. So we're going to pick your brain again in the future and try to get your help in synthesizing the emerging data landscape in prostate cancer.

Neeraj Agarwal: All I can say is this is the most exciting times for us as doctors taking care of our patients.

Petros Grivas: I fully agree, everything is for the patients and hopefully all these trials will ideally translate to meaningful results. I would like to thank you so much for your time and thanks very much for the audience for staying with us.

Neeraj Agarwal: Thank you very much for having me.