Alicia Morgans: Hi, I'm delighted to have here with me today, Dr. Mary-Ellen Taplin, who's a Professor of Medicine at Harvard, and a GU Medical Oncologist at the Dana-Farber Cancer Institute. Thank you so much for being here.

Mary-Ellen Taplin: My pleasure.

Alicia Morgans: Great. So you gave an outstanding talk here at APCCC 2019, and one of the best parts, from my perspective, was hearing all of the really relevant clinical pearls that you ended up bringing up, throughout your talk. So I'd love to touch on those. But before we even get there, your talk was a daunting one, or the topic was a daunting one, and you were supposed to talk about sort of sequencing and first-line treatment of mCRPC after either abi or doce or whatever AR targeted treatment you wanted to give in the metastatic hormone-sensitive setting. Tell us how you approach that.

Mary-Ellen Taplin: Well, so this particular topic, first-line treatment of mCRPC after patients have received either docetaxel or abi, enza, or apa, there's very little data to guide us. So that's the first thing. So the points that I wanted to make were it's really a clinical decision between the treating physician and the patient. And there are some clinical characteristics that I think the physicians can use to try to help guide the decision. I think the biggest, most important one, is how the patients did with their initial therapy. Basically, if they were treated with doce or abi, and had a very short response, that's a sign of embedded resistance and those patients tend to have shorter responses to the subsequent therapies. So, I think, if they got chemotherapy, it's reasonable to try either a different chemotherapy drug or an abiraterone, or enzalutamide, or apalutamide, but the patients should be watched carefully. If they had abiraterone for two years and became resistant, then it makes sense to me to try chemotherapy. But, in addition, there's many other approved therapies, like sipuleucel-T, like radium, other chemotherapies that could be appropriate for the patient as well.

Alicia Morgans: Like you said, just based on these clinical parameters that we think about, I guess.

Mary-Ellen Taplin: Right. So I think the data's going to evolve and, over the next couple of years hopefully, we'll have more information to guide us. Another point that I made, I think it's always reasonable to consider getting either a liquid or a tissue biopsy and trying to get some sequencing information that could inform either the first or the second-line treatment for mCRPC. For instance, if a patient has an alteration in BRCA gene or another DNA repair gene, it would be important to know that, earlier as you can to consider therapy with either carboplatin or a PARP inhibitor.

Alicia Morgans: Absolutely, especially as we have new data coming out, I think shortly at ESMO, really helping us to harness some of that personalized medicine approach to target things like BRCA2 or other DNA repair defects.

Mary-Ellen Taplin: Correct, correct. So I think all of those situations such as the clinical data, the genomic data, PSA doubling time, did the patient present with favorable disease initially, low volume? Had they been treated for local prostate cancer initially, which puts them in a more favorable category? Should be considered when you're choosing your first line therapy for mCRPC.

Alicia Morgans: Absolutely,

Mary-Ellen Taplin: Yeah. Unfortunately, one size doesn't fit all and that's where it becomes the art of medicine.

Alicia Morgans: Yeah. When I think- Unfortunately or perhaps fortunately because I think it allows us, we have the opportunity to sort of personalize, even if it's not targeting a particular mutation, it's targeting certain aspects of the patient or his tumor to make sure that we get the right drug to him. And I think it's probably a good thing because we have so many options at this point. Where there was a time when options were limited and we're looking to more options and some of the more practical pieces of your talk that I love were around using the options that we have even in ways that we might actually find in clinical practice are more common than you'd think. So things like dose reducing your Abiraterone or Abiraterone without prednisone, which everyone sort of gasped a little bit when you were talking about that, but you have some data on both of these scenarios that you shared with the audience.

Mary-Ellen Taplin: Yeah. Well, I'll say first off, that we generally like to recommend that people follow the label.

Alicia Morgans: Absolutely.

Mary-Ellen Taplin: And follow the data that's been generated in Phase III trials. But there are some Phase II trials that provide information that can be clinically helpful in practice. So we did a trial of about 60 patients using full dose abiraterone without steroids and had very careful algorithms of treating hypertension, including adding a first, a second, a third anti-hypertensive, treating hypokalemia. And we found that the majority, about 88% of the patients, did fine with full dose abiraterone without steroids, about 45% of them needing some support for hypertension or hypokalemia, usually grade one or grade two.

So if you have a patient who is in a special category, that you don't want to use steroids such as brittle diabetics, or a patient who's just personally opposed to steroids. This dataset gives you a guideline of what to tell the patient and how to manage them yourself. And I think the bottom line is they need to be monitored carefully. In this study, we monitor people monthly, so it may not be unreasonable to monitor them monthly, whereas in clinical practice they may be monitored every six to eight weeks, in that ballpark. So I don't personally use abiraterone without steroids very often, but I now feel like I have information that I can discuss with a patient in a situation that I want to use it.

Alicia Morgans: Actually, you and your team with Rana McKay as the first author published that data, was it Cancer 2019? So a recent publication.

Mary-Ellen Taplin: Yes, a recent publication. And the algorithms for following and treating the hypertension are in there. The hypertension can occur any time over the course of the abiraterone treatment, whereas the hypokalemia was usually seen within the first 100 days. So, it's awful, helpful information.

Alicia Morgans: Absolutely. Just to know when to expect to need those interventions. And you also talked about the paper that came out of University of Chicago, Russel Szmulewitz' work on the one tablet of abi with food. I have so many patients asking about that, and there are lots of drivers, either intolerance or financial toxicity or just I don't want to take four pills all the time.

Mary-Ellen Taplin: Right.

Alicia Morgans: So what are your thoughts on that?

Mary-Ellen Taplin: I think it's an interesting paper published in JCO recently, and it was randomized, it was small, 34 patients in each group, but 250 of abiraterone with food, versus full dose, 1000 milligrams. And at three months which was their primary endpoint the PSA responses, which was their efficacy endpoint, was pretty much equivalent. They did measure androgen levels which were castrate in both groups. The abiraterone levels were much lower in the lower dose ones, but it didn't seem to matter, at least at that three-month endpoint. What I suspect will happen over time is that the lower dose will lose its efficacy quicker and the dose may need to be increased over time.

Those of us who are old enough to remember, we used to use a lot of ketoconazole, which was also a sort of dirty CYP17 inhibitor, and we would go down on the dose, and then go up on the dose and then when the patient was getting toxicity go down again. And you could often, mitigate toxicity by fluctuating the dose up and down over time, depending on how the patient was feeling and what the PSA was doing. So abiraterone is hitting the same target and it's, probably would have a similar effect. Bottom line being a lot of patients can probably tolerate a lower dose with similar efficacy but with some concern for losing efficacy sooner than if they were on full dose.

Alicia Morgans: Absolutely. And that's what I tell my patients that really a 12 week PSA endpoint is exactly what it is. It's 12 weeks and it's only PSA. And so in terms of longer-term disease control and efficacy in terms of survival, we just don't have that data. Which was your message throughout much of the talk actually, but it can be reasonable. And I think as you mentioned that in the talk to just to have that knowledge and then to do some close monitoring of these patients because if the disease starts to take off at some point in it, we would want to be able to catch that. So any other clinical pearls that you want to share with the audience? Because I think these are really, really helpful. 

Mary-Ellen Taplin: One of the other ones is about flare. PSA flare or sometimes even PSA flare in the context of radiographic flare. That's a known reported phenomenon, about 30% of patients on chemo and perhaps 10% or so of patients on abiraterone. So I would caution people not to throw out drugs that could be working too early because of a flare situation. So follow the PSA's over time, follow the radiographs over time and only when there's clear radiographic progression would I consider stopping the medication.

Alicia Morgans: Absolutely. I tell my fellows that every year when I give a talk on how to start these oral agents and chemotherapies as well, that it is important. We wouldn't want to get rid of a potentially really useful therapy because we're misreading flare. So thank you so much-

Mary-Ellen Taplin: You're welcome.

Alicia Morgans: ... for sharing your expertise. I feel like I'm in fellowship again and learning anew. But I really appreciate your time and fantastic talk here at APCCC.

Mary-Ellen Taplin: Thank you. Thank you.