Optimizing Care in Localized Prostate Cancer - Mary-Ellen Taplin and Adam Kibel

Adam Kibel and Mary-Ellen Taplin join Alicia Morgans in a conversation about optimizing the care of men with localized prostate cancer, both systemic therapy, and surgical techniques and a combination of the two. They discuss the treatment landscape and their insights into what the field could consider for patients with localized disease.  

Biographies:

Adam Kibel, MD, Chief, Division of Urology Elliott Carr Cutler Professor of Surgery in Urology, Harvard Medical School Urology, Brigham and Women's Hospital, Division of Urology, Dana Farber/ Brigham and Women's Cancer Center Dana Farber Cancer Institute Lank Center for Genitourinary Oncology

Mary-Ellen Taplin, MD, Chair, Executive Committee for Clinical Research Director of Clinical Research, Lank Center for Genitourinary Oncology Institute Physician, Dana-Farber Cancer Institute Professor of Medicine, Harvard Medical School

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. Mary Ellen Taplin, who is a Professor of Medicine at Harvard Medical School and a medical oncologist at Dana Farber; as well as Dr. Adam Kibel, who is the Chief of Urology and a professor of surgery at Harvard Medical School. Thank you both for being here.

Adam Kibel: Thanks for having us.

Mary Ellen Taplin: Our pleasure.

Alicia Morgans: You two have both done a lot of work on optimizing the care of men with localized prostate cancer, both in systemic therapy and surgical techniques, of course, and on combining the two. I'd love to hear your thoughts on where things stand in the field and where we need to go to really do better in terms of curing patients with localized disease.

Adam Kibel: In the past, we tended to treat patients that had Gleason 6 prostate cancer surgically. What we found out over the past 20 years is those are probably the patients who don't need to be cured, they don't need to be treated. We spent a lot of time trying to identify which one of those are going to progress. At the other end of the spectrum, we have people with fairly high-risk prostate cancer, Gleason 8, 9, and 10 cancer, patients that have a maybe a little bit of extracapsular disease, node-positive disease. I think in the past, 20 years ago, people sort of wrote these patients off as being incurable, and they're not. We can cure them, but unfortunately, it takes multi-modality therapy to do that. What we need to do is try to integrate surgery, radiation, and systemic therapy into these patients' care paradigm in order to improve the cure rate in them.

Alicia Morgans: How do you think about integrating these things, Mary Ellen? I know the two of you actually work really closely in this high-risk population thinking about combining surgical techniques and potentially radiation, maybe systemic therapy. What is your approach?

Mary Ellen Taplin: We had the hypothesis about 10 years ago, that a next-generation androgen pathway inhibitor would change the response rates in localized prostate cancer. As you know, over the years, many trials had been done looking at drugs like Lupron or Zoladex alone or with old anti-androgens that really didn't show much benefit. I will give the caveat that most of the patients in those trials were the types of patients that Adam mentioned, the Gleason 6 patients, that we no longer even treat.

Our first trial, we looked at a drug called abiraterone, combined with Lupron, surgery, and prostatectomy. We did tissue analysis of the hormones and proved that the drug abiraterone was really starving these tumors of the androgens. The tissue levels were incredibly low.

Alicia Morgans: This is when you gave abiraterone for six months before surgery?

Mary Ellen Taplin: Correct, correct. Then, we really didn't know what we would see for pathology responses, but about 10% of patients had complete pathologic responses. Even though that number is fairly low, especially when compared to the neoadjuvant work in breast cancer, the patients who went on the trial were exceedingly high risk. 80% of them had Gleason 8 to 10. We allowed lymph node-positive disease. Then, another approximately 20 to 25% had one to two millimeters, three millimeters of residual tumor. We started to ask, question is maybe you don't need a complete pathologic response, but with this incredibly detailed pathology analysis that we do on these trials, maybe one to two millimeters of residual tumor is essentially equivalent to what a standard pathology review would call a complete response.

Adam and I, over literally the last 10 years, have done then a subsequent trial looking at enzalutamide, a trial subsequent to that looking at more intense androgen deprivation with enzalutamide and abiraterone. We just finished a trial that we're very excited about looking at abiraterone and apalutamide, asking additional question of what is the right amount of systemic therapy in the context of prostatectomy. We've been doing six months. In this last trial, we randomized patients to another year of hormone therapy, so one cohort got 18 months and the other cohort got the six months they got preoperatively. That's the first shot over the bough, as far as I know, nationally or internationally at looking at that question.

I maybe will steal Adam's thunder, but we are so excited that finally, after I think 12 years, there is a Phase III trial in this space looking at neoadjuvant and a little bit of adjuvant androgen-deprivation therapy with Lupron and apalutamide compared to standard Lupron with a primary endpoints of pathology response and metastasis-free survival, so big international trial, lot of excitement in the urology community that I can let Adam discuss.

Alicia Morgans: I'd love to hear about that because, for these neoadjuvant and perioperative-type trials where we use systemic therapies, it really takes such a collaboration between urology and medical oncology. How do you make that work? Just tell us a little about that.

Adam Kibel: I think the first thing is you need buy-in from everybody involved, both the medical oncologist and the urologist. I think the evolution over the past, I mean so much has happened in the past 20 years since I did my training where medical oncology in the GU space has gotten so much stronger and urologic oncology has gotten much stronger as well. That produces individuals that want to collaborate with each other and find a better mousetrap.

The data when it first ... docetaxel was only introduced in what, 2004? I mean it seems like ages ago, but that's 15 years ago. At that point in time, I mean a survival advantage of two months was hailed as this miraculous change. Right? Now, that's very disappointing. We want to cure some of these patients. The data would say for other diseases, like lung cancer, having urologist talk about other cancers is a little dangerous, but for lung cancer, breast cancer, bladder cancer; giving patients systemic therapy who have higher risk disease has been clearly shown to dramatically not improve survival by a couple of months but by years and cure patients that were probably incurable. The data in prostate cancer is actually backed that up. As we moved the treatment earlier and earlier in the disease process, we find that the survival advantage goes from 2 months to 12 months to 2 years. Hopefully, in this neoadjuvant space, we'll find that we cure these patients that potentially were incurable, but just because of the volume of disease could not be, was too much for the systemic therapy to overwhelm it.

I think the reason why it works now is we have drugs that work, we have a patient population that needs it and we have individuals both in the medical oncology community and in the urological oncology community that embrace this kind of multidisciplinary care. I mean, I think, in retrospect, it seems like, "Ah, it's so obvious," but at the time, I think it was a real leap of faith. Mary Ellen was really a pioneer in this space and I was really very fortunate to start to work with her on this, again, about 10 years ago.

Alicia Morgans: Absolutely. Mary Ellen, can you tell us a little bit about your thoughts on why systemic therapy six months prior to surgery or continuing on, why would that have such an impact? Then as you think about that, AR-directed systemic therapy, but also chemotherapy, because I've had patients who have high-volume disease. We've actually emailed about patients who have high-volume disease who say, "I want to get chemotherapy before my surgery because I know Mary Allen Taplin is publishing that systemic therapy can be helpful, can chemotherapy be even more helpful?" What are your thoughts on those things?

Mary Ellen Taplin: All really important questions. I think what the breast cancer space has taught us that these high-risk cases, while they may look localized by conventional imaging, there's often microscopic systemic disease. Unfortunately, we don't have the tools to locate where that systemic disease is. Could adjuvant or salvage radiation do the trick for some patients? But, a lot of times, we think that that microscopic systemic disease is circulating in the lymph system, the bone marrow, the bloodstream. Thus, only a systemic therapy is really gonna make an impact for these patients, thus systemic therapy.

The question you ask about what systemic therapy would be best for patients is really not known. Probably, an intense androgen-deprivation therapy approach alone will be adequate to impacts survival for some significant minority of patients, probably in the ballpark of 30%. Then, there are other patients who have a more adverse risk features such as a p53 mutation early on in their cancer where we might not have the right treatment for those patients at this time. Maybe chemotherapy, but chemotherapy data in other spaces in patients with more with mutations such as p53, RB or others may not be what is needed.

I'm participating with Adam with a trial that Martin Gleave has written called the GUNS trial, which is going to try to stratify patients by molecular markers into getting either hormones alone if there's androgen receptor abnormalities, chemotherapy if there's other types of abnormalities, or PARP inhibitors if there's DNA repair abnormalities. That would be, it's a fairly small trial, Phase II, but that'll be one again, shot over the bough of trying to tailor the patient's therapy. Patients with aggressive therapy, in whom we don't think we're going to cure with surgery alone or surgery and radiation to get a more unique approach to their tumor.

Adam Kibel: Can I jump in with one-

Alicia Morgans: Yeah, please.

Adam Kibel: ... aspect to this. I think one of the important aspects about multi-d care is we also know the patients, the type of patient a little bit better, not necessarily the individual patient, but the type of patient. Toxicity around treatment I think is really an important parameter for patients in this neoadjuvant and even adjuvant state because the patients feel great. I mean, they're coming in, they're saying, "I don't feel like I have anything wrong with me," and the vast majority of them now you're telling you have to escalate the treatment.

Having been involved in trials that gave docetaxel chemotherapy earlier in the disease process, the toxicity was hard on the patients. I think if we identify a patient we know is going to benefit from it, I'm not arguing against it, I'm just saying we have to balance that against the cure rate, that the androgen-deprivation therapy, including abiraterone, apalutamide, enzalutamide, et cetera; they do have toxicity. I don't want to say there's none, but it appears, at least to me, and I'm very interested in what both of you think, to be better tolerated than docetaxel in that particular patient who doesn't feel like they're ill in any way, shape, or form.

Alicia Morgans: I would agree with you. When you're thinking about using a systemic therapy in this setting, really minimizing side effects is important, unless you have clear evidence of a survival benefit. Sometimes you don't have the evidence until you enroll the patients. But, I would say a majority of the data, at least as we look at the low-volume metastatic disease and we look at non-metastatic CRPC, for example, or we even think about the STAMPEDE data in the non-metastatic patients; these areas seem to me to suggest a benefit from an AR-targeted approach, whereas they did not, like in the non-metastatic STAMPEDE population, did not necessarily suggest a benefit for chemotherapy, and the low volume, hormone-sensitive: no benefit, at least in CHAARTED, for chemotherapy. I agree and I think as we're always trying to balance toxicities with efficacy, these are questions that are going to be raised particularly in an asymptomatic patient population. 

I think this leads to my question for you guys as you think this through. As you were designing the Phase III trial that is looking at apalutamide in sort of a perioperative kind of a setting, one of the things that I think is really important is that you limited the duration of time to which the patient was exposed to treatment. Some studies, for example, the Messing trial, when we had a postoperative population, we had nodes positive and then it was indefinite ADT. Now, we look back and think, "Well, I'm so glad that you had a survival advantage, but goodness, what do I do with that data for indefinite ADT?" But, that's not how this trial's designed. Can you talk to me a little bit about that and what was your thought process in ensuring that there was a defined period of exposure for these patients?

Mary Ellen Taplin: Our goal is cure and with intense limited therapy, so intense systemic therapy, the best surgery and we leave it up to the treating physicians whether adjuvant radiation is something they want to recommend for the patient. Our intent wasn't to keep people on lifelong therapy. We, nobody really knows the right duration of androgen-deprivation therapy. You can extrapolate from the radiation data with high-risk patients that it's looking like 18 months, maybe as good as 36 months, a lot of people use 24 months. We've been very comfortable in our studies with six months, which was very controversial 10 years ago when we started doing it.

For our Phase III, we ended up with a year of therapy six months before and six months after as an adequate amount to be, really induce apoptosis in these tumors, especially the microscopic systemic disease. Our intent was not to make people permanently castrate for life. The longer you go with the androgen-deprivation therapy, the higher the chance goes that their testosterone won't recover, so that was what we were comfortable with.

Adam Kibel: I was going to say the ... I mean obviously this is a new space, so you don't actually know what's going to be the right amount of treatment and you have to take an educated guess. But, the idea of starting and stopping hormonal therapy again, 5, 10 years ago people would've said, "You're crazy." Now, we have the study from Canada and the SWOG trial, which has allowed us to define that maybe interim, in the rise in PSA state, castrate-sensitive, intermittent androgen deprivation is going to be as good as lifelong androgen deprivation. In the metastatic state, obviously we don't want to get into that controversy here, but it's not clear that it's better, right?

Alicia Morgans: Mm-hmm.

Adam Kibel: We sit here and we say, "Okay, so these high-risk patients who don't appear to have metastatic disease are probably closer to that rising PSA after definitive local therapy population where intermittent androgen deprivation was acceptable. If we go ahead and we treat these patients for a period of time, we cure some and there are some that have a recurrence and then they get put on additional therapy afterwards; I have trouble believing that we've done them any harm by having that stopping and starting, and we've clearly done a benefit to the patients who get it for a finite period of time and then don't have to start taking it again.

Alicia Morgans: Absolutely. Benefiting some, as long as we're not doing harm to the others is clearly a win and would change practice. Who are these patients? As you're in clinic, you're probably the one seeing these patients, Adam. Who are these patients that are the right patients for intensification, whether it's on this trial or other studies in the perioperative space?

Adam Kibel: I probably am seeing more of these patients, but as an institution, we've really embraced multi-d care.

Alicia Morgans: Great.

Adam Kibel: We have a high-risk localized prostate cancer clinic in which the patients see the two of us and also Paul Nguyen, one of our radiation oncologist.

Alicia Morgans: It's fantastic.

Adam Kibel: I think we're not alone in embracing that model. I think other places are as well. I'm sure you are as well at your institution. I think the patient comes in, who has this high-risk prostate cancer and they get to talk to all of us about what are the pluses and minuses at the same sitting so they can weigh the benefits. I think high-risk prostate cancer, in the next few years, is going to get sub-divided a little bit. I mean MRI fusion technology, where we're able to actually biopsy a lesion is now producing a lot of patients who have Gleason 8 cancer, that it's just a small focus of disease. I'm not saying that's not real disease. I think it is, but I'm not sure it's the kind of patient that is the patient where the old, systematic, 12-core biopsy had Gleason 8 in like 10 out of 12 cores. 

We've tried to include a volume, so they have to have multiple cores that show high-risk disease and no evidence of metastatic disease. We've also incorporated a little round PSA. If somebody has, say, Gleason 4+3 cancer in multiple cores, say six or more, and has a PSA over 20; that patient would also be included as well because we want patients who are actually at risk for developing metastatic disease because A, those are the patients we want to benefit and B, those are the patients that actually could have an event that we can prevent. That was the error in the earlier studies where they only included Gleason 6 cancers. Nobody was really at risk for failure, so it's really hard to prove a benefit when there's no benefit to be had.

Alicia Morgans: Absolutely. What would your closing message be for each of you to clinicians who are seeing patients with high-risk disease? What are your thoughts and what is your guidance at this point as things stand today?

Mary Ellen Taplin: I would just say one thing is that in the studies that we've done, the average age has been 58.

Alicia Morgans: Wow.

Mary Ellen Taplin: We see men in their late 40s to early 60s, and they have a lot to lose from their cancer and a lot to gain from an approach that may be innovative and could impact their cancer more. I would encourage the treating physicians out there to look for that group of patients, high-risk localized disease, younger age.

The name of the trial that we're doing is called the PROTEUS trial. Going to be open in 120 centers internationally so it might be a good opportunity for patients like that. A lot of people will have the trial available if not at their center, at other centers, and I believe we're still looking for centers so anyone can reach out to Adam or myself if they're a urologists that is active doing prostatectomies and seeing these patients.

Alicia Morgans: Fantastic.

Adam Kibel: I guess I have two messages. The first, a patient who has high-risk prostate cancer shouldn't be nihilistic about it. These are patients that are still curable. They still deserve an attempt at cure, and that's the message we should be delivering to the patient. The second message is we are incredibly enthusiastic about this approach and this trial, and I'm sure you are as well. But, it's a trial. An awful lot of studies get done that are negative, unfortunately.

I would encourage people not to do this off the books. We don't do it off the books. Patients come in and we don't have a trial open, we say, "I'm sorry, we're not going to treat you in a non-trial setting because we don't know that it's any better, and there is always the possibility that it's worse. You get the toxicity without the benefit." If you see these patients and you've gone ahead and seen this discussion, I wouldn't start putting all them on abiraterone and apalutamide or enzalutamide and then doing radical prostatectomy six months later. Find a center that's doing studies in this space or do the studies yourself so that we can move the field forward.

Alicia Morgans: Absolutely. I have to say, I mentioned before that Mary Ellen and I talked about patients who have come to me and said, "Well, I just want to have chemotherapy and everything before I go to my surgery."

Your response was, "Well, if they can't come to the trial, then they should get standard of care treatments," which is what my response was too.

But, I could say "I had a collaborative experience with someone else and we all agreed that you should get standard of care therapy and then you should continue," because it is possible that we won't be doing better, but it's also possible that we will be doing better, which is why we need patients and clinicians to engage in these trials and answer the questions. I commend both of you for your really wonderful interest in this space and your interest in getting these trials done so that we can answer questions for patients and for us to know what the right thing is to do. Thank you for your time today and for your hard work.

Mary Ellen Taplin: Our pleasure.

Adam Kibel: It's been a pleasure. Thank you.
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