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Alicia Morgans: Hi, I'm thrilled to be talking today with Dr. Mary Ellen Taplin, a friend and colleague who is a medical oncologist at the Dana-Farber and a Professor of Medicine at Harvard. Thank you so much for joining me today.

Mary-Ellen Taplin: My pleasure, Alicia.

Alicia Morgans: Of course. So, Mary Ellen, you are an expert in all things hormonal and have been for many years and I always love to hear your insights on that and I think one of the areas that's most rapidly changing in prostate cancer is the metastatic hormone sensitive space with lots of hormonal approaches as well as chemohormonal therapy being used in that setting to prolong survival. What are your thoughts in that area and how are you thinking through the data as it really continues to accumulate?

Mary-Ellen Taplin: Thanks for bringing that up, Alicia. It used to be easy for clinicians. A new patient came in, with metastatic prostate cancer and we immediately turned to androgen deprivation therapy alone, understanding that the response to androgen deprivation was going to be limited. So, the area has gotten more complicated with the new data that's come out and maybe I'll just pause and start from the beginning. A few years ago, the data from the CHAARTED trial was released, which demonstrated that treating these patients with a combination of androgen deprivation therapy plus docetaxel chemotherapy improved overall survival. So, that trial was led by Dr. Chris Sweeney and it was impactful for several reasons but two treatments that we had all been using for a long time, combining them and bringing them up earlier, really led to a substantial improvement in overall survival. It validated important endpoints for our patients.

And what was also interesting and unique about that data is the positive outcomes were not consistent across all patients with newly diagnosed metastatic hormone sensitive prostate cancer. It was a surprise to me that the benefit was not seen in patients with lower volume metastatic disease and to simplify it that trial defined it as four or fewer metastasis. So, at that point with the CHAARTED data, we were offering patients chemotherapy but primarily patients with a higher volume of disease. Subsequently, several trials show that the use of the drug abiraterone, which is a CYP-17 lyase inhibitor, so a compound that can more intensely block the synthesis of the androgens not only the synthesis of androgens from the testicles but from the adrenal glands and even from tumor itself as tumors develop resistance they can upregulate the CYP enzymes and produce their own enzymes.

So, these trials show that the use of abiraterone improved outcomes as well. Delayed metastasis, improved survival and unique to these trials, the benefit was across all patients with metastatic hormone sensitive prostate cancer. Those trials also included an early group of patients who didn't have metastasis, some patients with locally advanced prostate cancer and I would say we're evolving in our understanding of those patients. The early data showed delayed metastasis but we don't yet know whether those patients are going to have a survival benefit from the early use of abiraterone in that space. And I think it's a confusing space for clinicians right now. I know in my region, I see some radiation oncologists say that are early adapter and think that everyone in that space should get abiraterone.

And then others, including myself I’ll say, are still trying to process the data and understand which patients with localized disease should get abiraterone because you understand that abiraterone has a list of potential toxicities, needs close monitoring and is an expensive medication to use over a many year period. So, in conclusion, at least at this point in time, when a patient with newly diagnosed metastatic prostate cancer comes in, in general, if they have high volume disease, we'll talk to them about docetaxel or abiraterone. There's no data to date that supports the use of both drugs. Some patients like the idea of getting a limited amount of treatment with chemotherapy even though chemotherapy sounds more onerous but it's six cycles over four months and then they're done, except for continuing their androgen deprivation therapy.

Whereas other patients might choose the abiraterone over the long term with close monitoring and most people will do safety labs and blood pressure checks on it every four to six weeks basis when patients are on abiraterone. So, it's a commitment. There's going to be new data presented at ASCO, which will demonstrate to us the benefits of enzalutamide in these patients, a trial that was run by Dr. Sweeney and we participated in it here at Dana Farber. The trial's called ENZAMET and that trial will not only demonstrate the value of enzalutamide in metastatic hormone sensitive disease but the investigators on that trial were allowed to give the patients docetaxel if they wanted. So, there will be patients on that trial who have gotten docetaxel and enzalutamide, patients who have gotten enzalutamide alone and it will give us some insight whether a combined approach with a next generation androgen inhibitor and chemotherapy is better than one alone.

So, I think that trial will be important. It's a plenary at ASCO in a couple weeks and I would encourage everyone to pay attention.

Alicia Morgans: I agree with that. I think one of the questions has been, if we combine these treatments, the chemohormonal approaches plus the AR directed therapies, can we do better or are there at least some groups that may benefit from that, either in an additive way or maybe even a synergistic way? So, I'm really eager to see that. But the landscape is even more crowded and perhaps as a preview to ENZAMET, there was some data presented by Andy Armstrong, the ARCHES trial. It demonstrated that enzalutamide in the metastatic hormone sensitive setting could at least prolong radiographic progression free survival immature for overall survival.

Mary-Ellen Taplin: Correct, correct.

Alicia Morgans: But we have some hint of which direction that plenary may go, at least in terms of the enzalutamide. It's also interesting, in that study, I think that the patients were randomized versus not just an LHRH agonist or orchiectomy but weren't they also given another non-steroidal anti-androgen, so something like bicalutamide or flutamide as sort of combination androgen blockade approach, which is also kind of interesting that they made the control more powerful? So, hard to show a difference and really something that's also a key component of that trial.

Mary-Ellen Taplin: Yes. Bicalutamide was the control in that cohort, yeah.

Alicia Morgans: Absolutely. And then we also heard a press release that said that apalutamide in this setting, in the TITAN trial may also be beneficial. At least by the press release, it seemed to prolong radiographic progression free survival and overall survival in the metastatic hormone sensitive space, though I haven't yet seen that data but hopefully coming up soon. I think it may be also discussed at ASCO so we'll have to see.

Mary-Ellen Taplin: Yeah, of the next generation androgen inhibitors, if you look at what we know about efficacy, they'll never be combined head to head but it's not surprising at least to me that they would all be similar, enzalutamide, apalutamide, probably darolutamide, and you can't always expect what happens in metastatic castration resistant prostate cancer to have the same outcomes in hormone sensitive prostate cancer. However, what we know today in metastatic CRPC, really the efficacy of abiraterone and enzalutamide are very similar in terms of overall response rates, time to progression, benefits and overall survival. You can hypothesize that even drugs like apalutamide and enzalutamide will be similar to abiraterone in the hormone sensitive space.

Alicia Morgans: I agree. Well, and speaking on your experience too on sequencing these, we're using all these AR directed approaches in the metastatic hormone sensitive space now or we will soon be if we're not already I think, where you see that going when it comes to the metastatic castration resistant setting? You had some experience with the PLATO trial, thinking about sequencing these agents or combining these agents, so what are your thoughts when it comes to mCRPC after these novel approaches in the metastatic hormone sensitive space?

Mary-Ellen Taplin: Yeah, I think that cancer cells adapt quickly. What we know from tissue studies is that there is early adaption of tumor cells to resistance probably even before we're seeing that in the clinic in terms of changes in PSA response or progression radiographically. So, I think it's very possible and likely that these tumors that are exposed early to second generation androgen inhibitors will have developed resistance, resistance mechanisms, that will make similar approaches less effective down the line and we're going to have to get creative at looking at new combinations in metastatic castration resistance. Perhaps a drug like abiraterone or enzalutamide will be combined with something strategic, maybe strategic based on a genomic profile of a tumor but such as a PARP inhibitor, IO, EZH2 inhibitor.

Alicia Morgans: Mm-hmm.

Mary-Ellen Taplin: Other epigenetic modulators and hopefully one of those approaches will hit or we will get smart about parsing out our treatments based on what appears to be tumor growth signaling based on tumor profiling.

Alicia Morgans: Absolutely. Well, the metastatic hormone sensitive landscape is becoming more complicated but at the end of the day ADT is probably not, for most patients, standard of care alone or on its own anymore. Now, I think the standard of care is probably some combinatorial strategy with a GNRH agonist, antagonist plus either abiraterone or chemotherapy but that's changing. We may use other AR directed therapies in that setting in the near future as that data comes out. But it's important I think for patients to know that it's probably a little more than just a GNRH agonist or antagonist alone at this point, for most patients, and we'll see where things go in the future. ASCO's going to be very exciting. So, thank you so much for sharing your insights and talking this through with me.

Mary-Ellen Taplin: You're welcome. My pleasure.