The Changing Therapeutic Landscape of Prostate Cancer- Nicholas Vogelzang

May 12, 2019

Nick Vogelzang discusses a brief history of the advancements in treating prostate cancer.  He provides background on how we have arrived at where we are now with the advances in both the diagnosis and treatment of prostate cancer while talking with Alicia Morgans.  Dr. Vogelzang reflects upon the time when we were relegated to using primitive bone scans to define disease to the current era of advanced imaging with highly sophisticated techniques and believes that we are currently in the "pre-cure" space and we are finally approaching a cure for prostate cancer which we may achieve in the next 20 years.  He describes the balance between managing the patient who will benefit from early treatment.  He is concerned that he sees many patients not getting treatments that are approved in mCRPC, such as sipuleucel-T and radium-223.  He describes that so many patients are not being fully treated.  He concludes on a note of hope for the future of treatments.  


Nicholas J. Vogelzang, MD, FASCO, FACP, Associate chair of the Genitourinary Committee for US Oncology Research and Vice Chair of GU Committee SWOG, Comprehensive Cancer Centers of Nevada

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.

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Alicia Morgans: Hi, I'm thrilled to have here with me today Dr. Nick Vogelzang, who's the Chair of Medical Oncology at US Oncology Comprehensive Cancer Centers of Nevada, and also really big in SWOG, one of the roles that I think you've been most helpful to the rest of us playing. I'd love to hear your thoughts on where we stand right now in prostate cancer given the changing therapeutic landscape. Everything is really turned upside down. Where are we? Where are we going? 

Nicholas Vogelzang: Well, it's an extremely exciting time. It's one reason I'm never going to retire. I've seen prostate go from a disease where we were unable to define anything other than very primitive bone scans and no CAT scans, to now advanced imagining and highly sophisticated PSMA gallium scanning, et cetera. We're able to pinpoint the cancer. Unfortunately, we're still not able to pinpoint dormant cancer. The cancers that go dormant for years still are a challenge to us and volume of disease function related to treatment, et cetera. I would argue that we are moving into a pre-cure space, that we are able to cure many patients, even metastatic patients. We are approaching the cure. 

We don't have good tools to monitor it yet, but when you see patients with oligometastatic disease achieving seven, eight, nine year cure rates when you see node-positive patients never relapsing, there's a palpable optimism. My view is that we always think that moving drugs earlier is going to be helpful. I just wrote an editorial for JAMA Oncology in which I said I'm not sure where to put docetaxel in the advanced local disease. I know where to put it in metastatic disease. I'm not sure that we want to treat all our node-positive prostate cancer patients with docetaxel. Maybe yes, maybe no. What about PSA relapse? These are patients who may be curable with radiotherapy and hormones.

Do we need docetaxel there? I'm also intrigued by the whole prospect of lutetium. We are seeing high level responses in 30 to 50% of patients who are refractory to docetaxel and taxanes. That suggests that we, as I said earlier, need to move it earlier, but then you run the risk of damage to the bone marrow and long-term side effects and survivorship issues. We need to look at this as a possibility that we're curing patients with our current modalities judiciously applied maybe adequate for a large number of our patients. It's surprising to me that many patients are not getting the full spectrum of therapy. 

We find repeatedly that patients are not getting radium, that they're not getting sipuleucel-T, that they're not getting cabazitaxel. Even though we have these agents, we're not giving them to our patients appropriately. It may be that for some patients the full spectrum of drug availability should be applied. That's my number one point. The number two point is that with the increasing understanding of genomic landscape, we may be able to identify those patients with a variety of genetic abnormalities that will benefit certainly the DNA repair deficiency patients, but I'm intrigued by some of these variant of unknown significance patients. 

If you have a BRCA1 and a coding mutation that is an unknown significance, what does that mean? What about your check two? What about your PEL B, your RAD51 patients? Are they sensitive to chemo? Are they less sensitive? Are they sensitive to radium? Should we intensify therapy for them? These are all the exciting steps that we need to mine our data with linking genetic data to therapeutic data. We don't have that yet. We have a little bit of that with PARPs, but we don't have any of that with radium. We don't have any of that with docetaxel. I see a large number of patients who are African-Americans and they have exquisite sensitivity to docetaxel. 

We don't even have an idea about what that means. Should we be treating those men differently? Are there subpopulations of taxane-sensitive patients that are exquisitely sensitive to taxanes? Long-term response to taxanes. We have no biomarker for that. We have no way to judge that. I think we need to learn to optimize our current therapy. We also for example ... Oliver Sartor and I just reported or about to report that sipuleucel-T is particularly efficacious in African-American men. Remarkably so. The P value was .029 for benefit of sipuleucel-T in African-American men. Many of our therapies are not linked to a biomarker. 

On top of that, the new next generation imaging may give us even more clues. How good a CR is a CR? I mean, you know, come on, we've done myeloma for years and we now know we were never achieving molecular CRs. Maybe there is a step that we need to take linking advanced imaging to our best available therapies. Multimodality therapy linked to advanced imagining may tell us who are the CRs and who can then be de-escalated from therapy. For example, almost all of my patients with hormone sensitive disease go through a multi-agent treatment, including the primary, including if possible a consolidation of the bones either external or with radium. 

Then I stop ADT after 18 months and I watch and get them away from all the side effect of ADT. I think we've underestimated the side effects of ADT. Hypogonadism in an older man is not good. They fall. They break things. There's links to mental status changes. I am not a fan of long-term ADT. I believe that maybe we over emphasized the role of continuous ADT. Even though I'm on the paper, I really was hoping that intermittent ADT would have been better. Maybe we didn't study it the right way. Our tools weren't sensitive enough. 

But getting men through an intensive treatment and then giving them an opportunity to recover to normal, whatever that normal is, is I think a goal that we should all strive for. 

Alicia Morgans: Absolutely. Really understanding the heterogeneity of the patients and their diseases and trying to match the right intensity of therapy. One thing that you mentioned that I really want to pick up on and pick your brain about a little bit is the use of novel imaging strategies to really identify these CRs, whether that's for eventual de-escalation or whether that's even to define an endpoint for these early phase trials. Things like adjuvant therapy in high risk patients post-prostatectomy or post-radiation. Is there something you can see in the future as a possible intermediate endpoint? 

Right now we have MFS that we're using, but still, for some of those patients, they're not hitting that metastasis endpoint for years and years and years. How do you think novel imaging may come into play in that setting? 

Nicholas Vogelzang: Yeah, it's a real challenge. Right now we have this burden and the benefit of PSA. If the PSA is zero, we go, "Ah, good. We've achieved that," but we know full good and well that that is a very poor biomarker. We've looked at circulating tumor cells. Not so good. I think there's real opportunity for better biomarkers and I don't mean that in a throwaway sense. We need better biomarkers. I sit in the board of CARIS and we have optamer technology ... Aptamer, sorry, not optamer, but aptamer technology that can distinguish in the blood of breast cancer patients ER positive from triple negative from HER2/neu positive patients on the basis of a blood test. 

Well, if that's possible, it wouldn't be surprising to me that we can find that same biomarker in prostate cancer patients. When is a CR a CR? Intensifying to those patients, de-escalating to those who don't need ADT long-term is I think an important goal. I've now seen enough patients enter long-term complete remission radiologically and PSA wise and I have not yet started to think about advanced imaging in those patients. They can't get insurance to pay for it. Secondly, it's going to be enormously expensive. Fluciclovine and PSMA scans are not sensitive to PSA levels below one. 

Yeah, we do them, but you know, I always tell my patients, "If you're going to get a fluciclovine scan, it's probably going to be negative when you're below one. Likewise with the PSMA scans, probably not likely to be positive below PSA one." We don't have the imaging qualities or imaging characteristics to really identify the minimal residual disease population. I want to be like myeloma. I want to have 10 drugs that can eliminate every last clone and then I want to be able to still have transplant if we can't get them into molecular remission. Myeloma and the hematological malignancies have given us a path. 

We've not followed that path very well in prostate cancer. I think we can do that. It's going to take the next 20 or 30 years, probably not in my professional lifetime, but I would like to think that your generation can take us there, can get us to these long-term molecular remission tools, advanced imaging, better biomarkers, genomic characterizations, to identify patients for whom we can achieve a cure. As one of my mentors Tom Fry and Jim Holland used to say, there's only two types of cancer. It's either curable or pre-curable. I think we can find cures for these patients. 

Alicia Morgans: Well, with that message of hope and call to action, I just want to say thank you so much for your time and your incredible message. Thank you so much. 

Nicholas Vogelzang: Thank you.