Combination Treatment in Metastatic Prostate Cancer: Is the Bar Too High or Have We Fallen Short? - Kenneth Chen

May 24, 2023

Alicia Morgans hosts Kenneth Chen to discuss a Nature Reviews publication on combination treatment in metastatic prostate cancer. Chen explains the paper's inspiration was drawn from observing subgroups of patients failing to receive the established standard of care. Chen identifies factors that influence patients' access to effective treatments, including cost, reimbursement models, availability of therapeutic agents, and health economics varying across countries. While physician perspectives and a lack of biomarkers to determine who will benefit most from treatment intensification are also factors, Chen advocates for the need for the urology community to adapt and increase the adoption of established care standards, and raises the issue of differential access to cancer care.


Kenneth Chen, MBBS (S’pore), MRCS (Edin), MCI, DFD(CAW), FRCS(Glas), FAMS (Urol), Consultant, Department of Urology, Singapore General Hospital, Consultant, Division of Surgery and Surgical Oncology, National Cancer Centre Singapore

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to be here with Dr. Kenneth Chen, who is a consultant urologist at Singapore General Hospital and is joining me today to talk about a Nature Reviews article that he authored, really discussing Combination Treatment in Metastatic Prostate Cancer: is the Bar Too High or Have We Fallen Short? Love that title. Thank you so much for being here with me today, Dr. Chen.

Kenneth Chen: Oh, it's my pleasure, Dr. Morgans.

Alicia Morgans: Wonderful. Tell me a little bit about what prompted you and the co-authors on this paper to put forth this piece in Nature Reviews. I think it's a really important statement and I wonder, what was it that made you decide it was an important thing to talk about?

Kenneth Chen: Well, thank you very much. Well, the idea was really conceived when I was doing a fellowship with Professor Declan Murphy back in 2021 at Peter MacCallum Cancer Center. The GU oncology team then, we had a couple of referrals from other hospitals where patients came just on ADT monotherapy, and it was really in the setting of post a flurry of trials establishing a new standard of care for these patients. We were quite surprised and taken aback that there was this subgroup of patients who were still falling below the standard of care, and we thought that it would be nice to actually examine real-world data. When we did that, we were taken aback and we said, "Well around the world, this seems to be a phenomenon." So that was really the start of this journey and this review article. I think, in doing so, we really wanted to explore factors that might come for this trend.

Alicia Morgans: As you did this and you thought about this, what were some of the factors that you think led to these patients not really necessarily getting the treatments that we know are so effective?

Kenneth Chen: We know that the story is not that simple. We know that there are several factors beyond trial evidence that determine whether patients ultimately get treated with the drug. For example, patient access to therapies governed by cost and reimbursement models, availability of the therapeutic agents, dual location-specific health economics, and all of which might substantially vary among countries. I think the trend itself cannot be explained entirely by cost alone, because if that were the case, we should see a increased pattern of usage of docetaxel and abiraterone, which have been shown to be more cost-effective treatment options. But we are not seeing that as well.

When it comes to regulatory and reimbursement approvals, we know there is an important role in determining patient access to therapy. Data has shown a wide variation in reimbursement times for new drugs amongst European countries. In fact, the European Federation of Pharmaceutical Industries and Associations, Patients W.A.I.T. survey shows that the average delay between market authorization and patient access can vary from as little as 4 months to 29 months. And that's pretty substantial considering the time from evidence to time where we actually practice the evidence.

This effect of inequality in cancer care can be actually seen in the control arm of the LATITUDE trial. In this study, abiraterone was not provided by the trial in the CRPC setting. Does local access determine whether patients in the control arm could benefit from abiraterone at disease progression? And the difference of 8 months in overall survival within patients from Eastern Europe where abiraterone was available and patients from Western Europe were access to abiraterone was limited, provided direct evidence of the effect of differential drug access.

Well, going beyond this access, we do know that at Prostate Cancer Consensus Conference for developing countries, there were concerns about resource limitation for clinicians. And in fact, 64.9% of the panelists voted for combination therapy. But this response drastically dropped to 8.1% when the panelists were asked to consider practice in a setting of limited resources. So we're really talking about a multitude of factors which determine whether the patient ultimately gets access to the drug.

Alicia Morgans: I so appreciate you walking us through these different perspectives. One of the things that I remember from that Consensus Conference was, of course, talking to other physicians and the physician's perspective, and some physicians felt very strongly that they did not want to intensify, maybe because of their perceived burden on the patient or their thought that ADT alone would be sufficient for individual patients. I personally struggle with that because I can't tell for any individual patient if ADT alone is enough, and so I intensify for all patients who I think may benefit. But there were strong feelings and also feelings that they were protecting the patient in some ways. Is this something you talked about at all?

Kenneth Chen: Yes. Thank you for bringing that up, Dr. Morgans, and I would really like to develop that further. In fact, there have been some surveys among physicians, treating physicians on their perspectives, and exactly, we have some sentiments where intensification of treatment is not for everyone. This brings me to the next topic about whether there are adequate biomarkers at this stage to actually differentiate who will benefit most from intensification. And I think that's still lacking at this point in time, and that might be a very subtle factor as to why some physicians are actually holding back. Because if you consider cost of the drugs, resource limitations, it does make sense to actually intensify treatment for this really selected group of patients who really would benefit most from this approach. So that might be a factor which has not really been widely talked about among physicians, why some physicians are really not going all out for these patients.

Alicia Morgans: Yeah, I think that's a really nice way to think about it and to think it through. That we instinctively know from our clinical experience that there is such heterogeneity within these populations of patients and we're all on a spectrum of where the risk benefit lies, where we would make a choice to help that patient intensify versus not. And we're all sort of in a different place. As you think about this work, and you asked the question, are we really falling too short? Or is the bar too high? What's the answer?

Kenneth Chen: In coming up with the title of this paper, we wanted to adopt a very balanced view. As you can see, on one side, we could have, perhaps, been entertaining a very high standard, and we have not really taken care of various factors when pushing forward these recommendations. On the other hand, perhaps people are just not practicing according to the standard of care. So, we entertain these two thoughts at the start.

In reviewing all the several factors, I think we don't really have a strong conclusion. But what we do know is that, perhaps, this is just a matter of time before the rest of the urology community catches up with the standard of care. And we know from the diffusion of innovations theory that with any innovation or any new idea that is rolled out, there will be the early adopters and the late adopters. This is a phenomenon across various industries. So perhaps we're just waiting for the swell of treatment intensification that has yet to come. It's just that the evidence is not that new anymore and we really should be seeing a wider adoption of these recommendations. This paper is really also to raise the alarm bells on these real-world treatment patterns and to call the urology community to do more for this group of patients.

Alicia Morgans: Well, I think it is a wonderful sentiment. It's so important to raise this issue. Very nicely written and with the balance that you sought to achieve. I sincerely hope that we rise to meet that bar, because I don't think it's too high, personally. Though, the bar needs to be adapted to the location where the treatment's being delivered. And certainly we aim to ultimately adapt that bar to the patients themselves. As we understand the disease heterogeneity, we'll be able to make a bar that's right for that person. Thank you so much for your time and for your expertise. I sincerely appreciate it.

Kenneth Chen: Thank you so much. It has been a great pleasure, and thank you once again for the warm invitation.