APCCC 2019 PRESENTATION SLIDES

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Follow Up of ADT Alone vs. ADT "Plus" Presentation - William Oh

During the Management of Metastatic Castration-sensitive/naive Prostate Cancer session at the 2019 Advanced Prostate Cancer Consensus Conference, William Oh presented the use of androgen deprivation therapy (ADT) alone vs. the use of ADT in addition to one of the available systemic therapies for metastatic prostate cancer. 

Biography:

William Oh, MD Chief of Division of Hematology and Medical Oncology, Deputy Director of The Tisch Cancer Institute, Professor of Medicine and Urology at Icahn School of Medicine at Mount Sinai in New York

Related Content:

Written Coverage and Download Presentation Slides: Follow-up on ADT Alone vs ADT "Plus"



 

Read the Full Video Transcript

William K. Oh: Thank you. Thank you Silke and Aurelius for the invitation. I was working on my slides until about 10 minutes ago. These are my disclosures. Just an update on the cancer death rates in the US and some of you have seen this. I've put up these slides for the last decade. You can see the slight inflection upward, which is a little bit concerning considering all of the advances we've had. One of the questions obviously is the patients who are dying are dying in this state, so we have to continue to focus on this category. The question being asked in my talk was, what is this transition? How do we follow these patients as they go from metastatic hormone-sensitive disease to the transition to CRPC? I'm going to start with a case.

This is a patient I just saw a month ago. 65 years old presented in 2015 with pain, bone mets, Gleason 9 intraductal features, a PSA of a hundred, extensive bone mets, and some pelvic lymph nodes. At another institution, he started chemotherapy and ADT. Didn't complete it. His PSA had declined to 2.6. But because he hadn't completed the chemotherapy and because he had a persistently elevated PSA, he was treated kind of à la ENZAMET before ENZAMET was available. He started enzalutamide. His PSA actually continued to decline over the next three years slowly. You can see the PSA curve. It's hard to see the low levels, but they've continued to decline, but have never become undetectable. You can see he was been on enzalutamide the entire time, feeling well, working, and normal LFTs. The three scans that were done were at baseline about a year and a half after his diagnosis, and then the ones I'm going to show you in a minute.

One of the questions that we... We've talked a lot about next-generation imaging, but we actually don't talk about the frequency of how often we should do any imaging. Just routinely... Actually, in preparing for this talk, believe it or not, I'm going to show you some data that made me somewhat concerned that I have to repeat his scans because I don't routinely repeat scans on an annual basis. There seemed to be no necessarily reason to. He had multiple new liver lesions. His LFTs were completely normal and his PSA right after I did this scan started to rise.

One of the questions is, how closely should we be monitoring patients on therapy? Certainly, if we follow them very closely we might be able to improve disease control by switching earlier to a more effective therapy. We can reduce the risks of the treatment we have them on. We can reduce the cost of those treatments, but we don't really understand a lot about follow-up imaging. As we all know, there may be false-positive imaging, disease flares that we have to explain away if we don't think that they are real. Certainly some maybe insignificant progression, slow rises in PSA that we might treat through anyway. Also, patients are still concerned about the risks of imaging and the costs.

There's no strong evidence that detecting treatment early... Progression on treatment early is beneficial. Some of you may have seen the RADAR group. This is Dr. Crawford and his colleagues, some of the members on the panel, have met several times now to talk about the use of imaging in metastatic disease. You can see the first three elements there I think we'd all agree with. The doubling of PSA since the last imaging, symptomatology, performance status. But this was a curious one, you know? It was a consensus meeting. Every six to nine months in the absence of a PSA rise. Maybe during the panel we can talk about whether this is what people do or where this recommendation even came from.

I dug into the NCCN guidelines and this is actually the page that is the guidance on imaging. It's very, very hard for an average clinician to be able to look and find what the recommendations through NCCN are for imaging or routine imaging. This is what it says, "Bone scans should be performed for symptoms," I think we all agree, "And as often as every six to 12 months to monitor ADT." I don't do bond scans every six to 12 months on ADT. "The need for soft tissue images remains unclear," I think that's absolutely untrue, "And in CRPC, eight to 12-week imaging intervals appear reasonable," which I think is also not reasonable.

It's very interesting. These are consensus documents, and I think this is buried in a part of this very complicated guideline that an average clinician really doesn't have any good guidance on. The paper that made me actually do the scans on my patient was this paper that Tom Beer... I'm not Tom Beer as you see. Part of the discussion here was how often should you follow these patients with imaging. This was a PREVAIL post-talk analysis. Of the 872 patients on PREVAIL who had progression on radiographic imaging, about a quarter of them did not have a rising PSA, which was really a surprising number.

If you actually look, it's a little complicated, you can see the first column, the 65 patients who had a non-rising PSA, when they enrolled in the study, their PSAs were actually higher. They actually enrolled more often because of PSA progression. The likelihood of having a non-rising PSA was actually inversely correlated before going on enzalutamide to the reason they went on the study in the first place.

If you looked at the type of progression they had radiographically, actually about over a third had soft tissue progression even if they had started enrolled on the trial in PREVAIL because of bone only progression. There's clearly a biological evolution going on.

For the first part of my talk, the summary is that there really seems to be in my mind no consensus regarding the frequency and certainly we heard in this meeting the type of imaging in mHSPC. I will say that the data from early CRPC suggests that we may be overreliant on PSA to determine progression and that as many as a quarter of patients may actually progress without a PSA rise. Should we be doing routine CT and bone scans, and how often should the NCCN guidelines be updated, and really is the biology of occurrence being altered by the use of these therapies themselves? Is this a Schrodinger's cat? Are we changing the natural history of this disease by the types of therapies that we're giving?

The second topic I wanted to cover is illustrated by this patient. This is a man who presented with rectal pain, Gleason 8, multiple bone mets and pelvic nodes again. He had hypertension on two meds and a distant history of a seizure disorder. He started ADT and abiraterone per latitude and his PSA declined. But after about six months, he developed chest spasms. He had multi-vessel coronary disease and three cardiac stents were placed and the abiraterone was stopped. He's followed at another institution. We're in New York, so people actually go to multiple hospitals at once. Actually he held it for about six months, but his PSA started to rise and his oncologist resumed half dose abiraterone really for CRPC obviously at that point.

What's the point of this section really in followup? These are four of the androgen receptor-targeted therapy studies (STAMPEDE, LATITUDE, ENZAMET and TITAN) that we've been hearing about and the duration of therapy in the last column. I mean, these are long durations of therapy for these patients. These are actually the medians at the time they were reported, so it's very possible that these numbers are even longer, two to three years or more on these combination ADT plus AR targeted therapies. This is an old slide I've had and I've updated for ADT alone. We know about all these side effects, and we know about the side effects that are highlighted here in particular, the cardiovascular risks, the cognitive issues and osteoporosis, which we're going to hear in the next session, for ADT alone.

What happens when you use these more potent androgen receptor-targeted therapies? We know enza has eight times the binding affinity to AR compared with bicalutamide. What does that do to the long-term complication rate with ADT alone? What's the impact of the duration of therapy? Do we have any idea of what these combinations are going to do to those known side effects? What's happening in the real world outside of these highly selected populations that go on these trials?

This was a nice review article published in Clinical GU Cancer of the cardiovascular toxicities. On the top you see all cardiovascular toxicities in the major trials using AR targeted therapy. On the bottom you see high grade. Affirm I think was the outlier here. Most of these trials, including with enzalutamide and abiraterone, really are to the right in terms of cardiovascular, favoring control. Meaning that there's I think a significant risk up to almost 1.8 fold higher risk of serious cardiovascular toxicities. Then this is another topic that I think Chuck Ryan's going to be talking about, which is do ART therapies increase dementia. I can tell you that whatever you believe about these studies, the patients are very concerned about them. I think we have to get our hands around the difference between cognitive issues versus true dementia and what is the effect of combining enzalutamide or abiraterone or any of these drugs for extended periods of time in these patients with this type of toxicity.

This is Bertrand's table from ASCO, which I think highlights something that we've all underappreciated, which is the risk of osteoporotic fractures in patients who are treated with these AR targeted therapies. I think a lot of it may be aggregated by the use of bone protecting agents, but these are certainly concerning and certainly causing morbidity in our patients.

Then there's this interesting review, really mini-review, that Matt and Maha wrote with this medical student that I worked with at Mount Sinai around what happens to intermittent therapy. We know intermittent therapy is a way to reduce the toxicities of these treatments, but their conclusion I think a fair one is that intermittent androgen deprivation is not the standard of care for metastatic hormone-sensitive prostate cancer in an era where we have seen really unprecedented survival impact from these combinations. I think we're going to need more information to really understand this.

To summarize this area, AR targeted therapy has clearly moved earlier, we know this, including mHSPC, but also M0 CRPC, and patients are being exposed longer at greater cost and toxicity. But how can we manage these complications while maintaining the benefits of therapy? This is one of the key issues in terms of the followup.

Then finally, I have only one slide on the issue of what treatment next. I think Mary-Ellen Taplin's going to have a whole 10 minutes on this. Very complicated with really a data-free zone. If a patient goes on docetaxel initially, if you see the little color-coded boxes, I usually switch therapy. If there is a short response to ADT plus docetaxel, if it's an intermediate response or a longer response, my treatment of choice is to switch mechanistically the drugs. But I think there's an argument to be made for other options, particularly in patients who have a longer response to that primary therapy. The opposite is also true. ADT plus abiraterone, I will typically switch to chemotherapy. But I think again, one can make arguments around the others.

Then, in the end, ADT alone, you can really do whatever you want I think. I understand in many third world countries, people are still not getting these next generation options up front, and I think we have to change that. This is Mount Sinai. Visit me in New York if you come by. Thank you very much.

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