Clinical Implications of TITAN in mHSPC - Kim Chi and Michael Morris

Kim Chi, MD discusses the first results from TITAN, A phase 3 randomized, placebo-controlled, double-blind study of apalutamide (APA) versus placebo (PBO) in men with metastatic hormone-sensitive prostate cancer (mHSPC), with Michael Morris, MD, and Alicia Morgans, MD. TITAN was designed to accrue patients with prior treatment for localized prostate cancer or prior docetaxel for mHSPC were allowed including patients with either high volume and low volume disease. Approximately 11% of the patients had received prior docetaxel. The co-primary endpoints included overall survival (OS) and radiographic progression-free survival (rPFS).  1052 patients with mHSPC were randomized to receive either APA + ADT or PBO + ADT.  This first planned OS interim analysis took place after about 50% of expected events. In this analysis, 525 patients were randomized to APA and 527 to PBO. The median age was 68 years; 8% had prior treatment for localized disease; 11% had prior docetaxel. 63% and 37% had high- or low-volume disease, respectively. At median 22.6 months of follow-up, 66% APA and 46% PBO patients remained on treatment. APA significantly improved rPFS (HR, 0.48; 95% CI, 0.39-0.60; p < 0.0001), with a 52% reduction in risk of death or radiographic progression and benefit was observed across all subgroups analyzed. Median rPFS was not reached in the APA group and 22.1 months in the PBO group. APA also significantly improved OS (HR, 0.67; 95% CI, 0.51-0.89; p = 0.0053), with a 33% reduction in risk of death. Median OS was not reached in the APA or PBO group. Time to initiation of cytotoxic chemotherapy was significantly improved with APA (HR, 0.39; 95% CI, 0.27-0.56; p < 0.0001). Based on these results, the independent data monitoring committee recommended unblinding to allow crossover of PBO patients to receive APA. Rates of grade 3/4 adverse events (AEs) (42% APA, 41% PBO) were similar, and discontinuations due to AEs (8% APA, 5% PBO) were low. The experts also discussed the clinical impact of the ENZAMET Study and the role of triple combination therapy consisting of ADT, novel AR-directed therapy and docetaxel given the data to date.

Biographies:

Michael Morris, MD, Medical Oncologist Clinical Director, Genitourinary Medical Oncology Service & Prostate Cancer Section Head, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY

Kim Chi, MD Professor, University of British Columbia, Medical Oncologist, BC Cancer Agency, Vancouver, Canada

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

 
Read the Full Video Transcript

Alicia Morgans: Hi. I'm thrilled to have here with me today Dr. Kim Chi, who is a Professor and medical oncologist at BC Cancer in Vancouver, Canada, and Dr. Michael Morris, who is the Prostate Cancer Section Head at Memorial Sloan Kettering. Thank you both so much for being here with me today. 

Michael Morris: Thank you, Alicia. 

Kim Chi: Thank you. It's a pleasure to be here. 

Alicia Morgans: Wonderful. I wanted to speak with the two of you about some practice-changing information that has recently been presented, actually, you presented, the TITAN data. Can you give us an overview of the trial, the population? What happened? What were the outcomes, and why should we be so interested?

Kim Chi: Well, the TITAN trial was a randomized, double-blind, placebo-controlled trial that was evaluating apalutamide which is a next-generation androgen receptor antagonist in patients with metastatic castration-sensitive prostate cancer. Now, the intent of the study was to accrue a broad spectrum of all-comer patients. It included patients that had one or more bone metastases on bone scan, and they could have high volume disease, low volume disease. They could have received prior chemotherapy and so on. That was the intent. 

1,052 patients were enrolled and randomized, and they received either apalutamide at standard doses, 240 milligrams daily, plus standard ADT, versus placebo plus standard ADT. The dual primary endpoints of the trial were radiographic progression-free survival, as well as overall survival. At the first interim analysis for overall survival, which was also the final analysis for radiographic progression-free survival, we found a survival benefit with a 33% reduction in the risk of death. 

There was also a benefit in radiographic progression-free survival. At two years there was an absolute 20% difference in the survival between the two groups. Both dual primary endpoints were met. At that point, the independent data and monitoring committee recommended the trial to be unblinded, and the patients on placebo crossed over. 

Alicia Morgans: Wonderful. One of the things I think that we're all thinking about, in addition to the fact that it looks like another AR-directed therapy seems to benefit patients with metastatic hormone-sensitive or castrate-sensitive disease is that there were a number of patients in this trial who actually got dual therapies, so they had docetaxel per standard of care at the time of enrollment or right prior, just prior to their apalutamide. I'm wondering what percentage of patients actually received docetaxel in this trial, and can it answer questions for us about whether triple therapy is the way to go in the future?

Kim Chi: Yes. That's correct. Patients were allowed to have received prior docetaxel, prior to enrolling on the study. It was about 10% of patients in both arms that received docetaxel. What we saw on subgroup analysis in these patients for radiographic progression-free survival is that the trends for benefit were consistent with the overall study results for both radiographic progression-free survival and overall survival, although the hazard ratio and the 95% confidence intervals were wide. This is reflecting the small subgroup of patients and the few events that have occurred.

Alicia Morgans: Probably too early to make conclusions one way or the other. In this trial, because the subgroup was pretty small, I don't know that we'll be able to answer that question. 

Kim Chi: No. I don't think we'll be able to answer the question, although it provides some evidence that in terms of the radiographic progression-free survival that there could be a benefit of adding apalutamide after docetaxel has been given to a patient. 

Alicia Morgans: True. Michael, I'm just curious from your perspective, and I know you've been watching all this data unroll, and participating, I'm sure, in some of these trials. What are your thoughts about treatment in the metastatic hormone-sensitive setting?

Michael Morris: I think that's the most important question now for the average practitioner out in the community, and even in academic centers is we have now a number of agents from which to select, and the question is independent of patient reimbursement and independent of financial issues, which is the best drug to go with? What should we choose? What gives the patient the most longevity for the best quality of life? 

I'm interested to know what Kim's perspective is on this. If you pull the lens out from your excellent presentation yesterday beyond any single drug, how are you making that choice in terms of your own patients as to what you'd prefer?

Kim Chi: Well, right now we have the choice between docetaxel and the benefit was mostly in high-volume disease from the CHAARTED study. We have LATITUDE which has shown benefit in both high risk as well as low-risk patients from the sub-analysis of the STAMPEDE study. Now, we have apalutamide showing both radiographic progression-free survival and overall survival in a broader selection of patients.

These are all very different medications in terms of their mechanism of action and toxicity profile. For docetaxel, I think the use of docetaxel's going to be declining because of the toxicity associated with chemotherapy. In our experience in a population-based analysis, over 20% of patients were experiencing febrile neutropenia with the treatment. We've seen quite a changeover for patients now receiving abiraterone. However, abiraterone also has its challenges. It requires frequent monitoring, monthly monitoring, initially every two-week monitoring, hypertension, elevated liver enzymes, and the requirement for the use of prednisone.

Then we have apalutamide and we'll soon perhaps have enzalutamide as well, have that ease of use, less monitoring. However, they also have their challenges. Apalutamide induces a rash in about 27% of patients. There's also the issue of hypothyroidism. Enzalutamide may have issues with fatigue. It's going to come down to a personal choice with the patient, discussing what's best for that particular patient, and their pre-existing comorbidities. 

Michael Morris: From my perspective, it would really help with this decision if we had really two key pieces of information which right now we're missing. The first is what's the biologic characterizations of a tumor that might lend themselves to one therapy or mechanism of action as opposed to another. The other is a question that's near and dear to your heart, which is which of these therapies represents the best value, both to the patient and to society as a whole. Which of these offers the shortest amount of therapy for the most gain in all of those important domains?

To date, really the only data that I've seen on this has come from the STAMPEDE group who has several of these therapies by which they can compare the social costs. Of course, social cost is context-dependent. What would be really nice is if someone were to make an analysis across these various modalities, and I think that we do need a lot of corporate participation to release those datasets, to assess such factors as time off from work, quality of life, time away from your family, the visit intensity, amount of laboratory testing, all of the things that you just mentioned, and do a comparative analysis as to which therapy offers the greatest benefit and value.

Alicia Morgans: I think what might be interesting, too, is that as individual patient circumstances differ, some of those value judgments and some of those costs actually may differ as well. For a retired person, perhaps time off of work is not as important. Perhaps, for another whose children have to take him to the physician's visit, it's the child's time off of work, or childcare costs related to that. It's really interesting how these analyses can be so specific to an individual patient. 

I love the idea of bringing in not only the adverse events, the patient-reported outcomes, as you said, and this X factor that I sometimes think about, these things that we don't really add up when we're thinking about these things. Thank you for considering that, Michael.

Michael Morris: The X factor is frequently not brought into the clinic, but is really deeply impacting the patient in real life. 

Alicia Morgans: I agree. Until we get that multi-institutional and maybe pharma-academic collaboration together, what are you choosing Dr. Morris? Are you choosing docetaxel, abiraterone, or imagine you had them, enzalutamide or apalutamide?

Michael Morris: Well, I make those choices, although I have to say that I feel uncomfortably under-resourced in terms of actual data to support those criteria. I do tend for the high-grade, low-PSA producing, viscerally-oriented P53 mutated, RB-deleted cancer, to err on the side of chemotherapy. Many patients push back against chemotherapy, and then I do think that you are down to those real details of a patient's priorities in terms of the various side effects of enzalutamide versus the inconveniences and side effects of abiraterone. 

Those are on a really individualized basis, touching on fatigue and cognitive effects. Again, I think that this is squarely in your domain. Hopefully, we will be getting data from your upcoming study comparing darolutamide with enzalutamide to see head-to-head prospectively what those might be. We may then feel like we're making those decisions not on a gestalt basis, but actually a data-based basis. The same goes for the biologic characterizations of one kind of cancer versus another.

Alicia Morgans: Absolutely. Kim has actually done some nice work in this area as well, leading to some understanding of the fatigue factors, looking at abiraterone and enzalutamide-treated patients. 

Kim Chi: Yeah. We compared directly abiraterone and enzalutamide and did quality of life analyses, including a crossover. Fatigue was an issue with enzalutamide. As well, quality of life declined with enzalutamide compared to abiraterone. This seemed to be isolated to the older patients, for those that were greater than 75 years of age. 

Alicia Morgans: That was a very nice-

Kim Chi: While those that were younger, the quality of life was the same. 

Alicia Morgans: It's really interesting to me that that paper is one of the first that really pulls apart, really tries to identify vulnerabilities in patients or patient subgroups that may have more or less of these side effects. Exciting work and I look forward to more work in that arena. I think that one of the other questions, the final one that I'd love to hear your thoughts on before we go is a question that was asked repeatedly at your presentation. Dr. Chi, if you gave a patient docetaxel, after the docetaxel would you then right away add on something like apalutamide? Because that was allowed in your trial and you showed a benefit. 

Kim Chi: If I had the availability, and at this time I would. It was this exact patient that Mike's talking about, those that have these aggressive diseases, high Gleason scores, nasty genomics that we want to give the best therapy upfront. We do give those patients docetaxel, and I would be quite compelled to give them apalutamide afterward, given the current knowledge that we have.

Alicia Morgans: We don't necessarily know that it's the best to add that on, and so I would love, but I appreciate your opinion, and I don't know the answer either, so I'd love to hear Dr. Morris. What do you think? Would you treat that patient right away?

Michael Morris: I'm not quite as confident as Kim is. I think just because you open the door to the question by allowing those patients onto the study, does it mean you have the answer at the end of the trial? The trial wasn't designed to answer that question specifically. I do think as was brought up in the meeting, you do need a test of interaction to see whether or not you really do have a readout there. I would like to see, remember that for this trial it was, what, 11%, was it, who ...

Kim Chi: 11% had prior docetaxel.

Michael Morris: ... had gotten docetaxel. In the other trial, with enza, it was under 20%. We usually would not draw a clinical conclusion based on just seeing similarities in a retrospective analysis in which the subgroup appeared to be performing at the same level as the group. Usually, we'd get a powered analysis in order to really change the standard of care. 

Again, I think it really depends on the patient who presents. A real discussion with that patient about what I consider to be real uncertainties. I do think that one needs to consider that if you're going to do docetaxel and then obligate the patient to a drug that is going to cost that patient 10,000 or more a month, that that's a real discussion on the certainty of the data. Not to mention the cost in terms of quality of life.

I myself feel uncomfortable saying, "Yes, we're ready to declare this a new standard of care, even for a given subgroup of patients." I really would like to see more data on this, and more analysis that's subject to real statistical rigor, as opposed to we let the patients in. We opened the door to the possibility, and therefore we conclude that we have a new standard of care for an identified patient population.

Alicia Morgans: I think this question will continue to rage because I think that there are going to be clinicians on both sides of this issue. I as the moderator choose to not answer for myself. We will let that go. Yes. 

Kim Chi: There will be data coming along, and, to Mike's point, we will have studies. The PEACE-1 trial, the ARASENS trial with darolutamide with docetaxel. Those will be the definitive studies. At this time, when you're faced with a patient in front of you I think there's sufficient evidence to have that discussion and make that choice with that patient.

Michael Morris: I'd agree that it's sufficient evidence to have a discussion. 

Alicia Morgans: Good. We agree. We agree. Wonderful. Well, thank you so much both of you for taking the time to share your inside thoughts on the Titan trial, and your expert opinion. I sincerely appreciate it and thank you.

Michael Morris: Thank you, Alicia. 

Kim Chi: Thank you.

Michael Morris: Thanks for having us.
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