Alicia Morgans: Hi, I'm so excited to talk today with Dr. Neal Shore. We're really reviewing the recent FDA approval of darolutamide in the metastatic hormone sensitive setting in combination with docetaxel on ADT. Thank you so much for being here with me today, Dr. Shore.

Neal Shore: Great to be with you Alicia, thank you.

Alicia Morgans: Well Neal, it's great to talk with you about this approval, which as I just said, is really in combination with docetaxel in the metastatic hormone-sensitive setting. What does that mean for you in your urology practice? Talk us through the data and its implications, please.

Neal Shore: Yeah, this is a really important, and very, very key right now for all of my colleagues in urology in the US, and really globally. And hats off to the FDA for getting this approval based upon the really great presentation that was done at ASCO GU 2022, in a pretty quick time. So, the FDA saw the data from ARASENS, it's clearly clinically significant. It was obviously statistically significant. ADT docetaxel with concomitant darolutamide versus ADT docetaxel as the control arm in mCSPC patients has a now obvious survival benefit, an RPFS benefit, a delay to CRPC, a delay to pain, multiple other secondary endpoints.

The implication for urology is we have to now really clearly have that wanted patient/physician shared decision-making conversation. Triplet therapy is now a standard of care for patients who can tolerate chemotherapy. You know, and I've been a big fan of using docetaxal since really 2007, and one of the things that I think most urologists, and sometimes patients forget, is actually how well tolerated it can be. It's only six infusions. It's given over a four month period. Our patients with mCSPC tend to be younger than mCRPC. They have a better performance status. But what ARASENS teaches us is that these patients do better than patients receiving traditional couplet therapy, or doublet, with ADT and doce.

Hats off to the steering committee. When this trial was started, this was in the very early days, before we saw the benefit of couplets. ADT and an androgen receptor blocker, whether it was Abi or Enza or Apa, so this is remarkably important, this data. And the fact that the FDA has now approved triplet therapy, inclusive of darolutamide.

Alicia Morgans: Well, I think it's really, based on that 32% reduction in mortality that we saw with the addition of darolutamide to the ADT docetaxel arm, and I think what's so important to your point too is that this was a very active control arm. ADT and docetaxel, at that time when the study was designed, was really the best that we had in terms of combination therapy for metastatic hormone sensitive disease. So to see that improvement in survival on top of that very active control combination I think is so impressive, and so important for our patients, particularly those patients with de novo metastatic disease. And in this trial, about 86% of patients had de novo metastatic disease, a setting that we know often has a poor prognosis, a faster progression to castration resistance, and something that we really need to do all that we can to slow down and stop that progression.

Neal Shore: I fully agree. We're seeing a lot more patients present now with metastatic disease. There are multiple reasons. One can bring up the controversy about not doing enough screening, the controversy around recommendations that have evolved over the years with the USPSTF. But additionally, just the aging of the population. So there's a correlation with more prostate cancer, and more MCSPC. The thing I think for my urology colleagues to recognize here is that if you're not offering triplet therapy, then you're not now practicing a state of the art medicine. We see many colleagues still using mono therapy ADT for MCSPC, despite the fact that we have now eight or nine trials demonstrating the level one evidence in mCSPC of a combination therapies.

So ARASENS is the most recent trial to now clearly demonstrate. FDA has said "We approve this for triplet therapy." And so I really want my urology colleagues to work more hand in glove with their medical oncologist if they're not comfortable with administering docetaxal. They should work very comfortably with their community or academic colleagues, and offer patients the best opportunity for life prolongation. And as you've also demonstrated in a lot of the work you've done is docetaxal often times helps improve patient's quality of life. They actually feel better, especially when they're symptomatic.

One of the really nice things that came out of ARASENS was it was complimentary to the work that we did in ARAMIS, and other trials, demonstrating the safety and tolerability of darolutamide. And really, there was essentially no difference between the triplet arm versus the couplet arm in the ARASENS trial. I think it's really important for my colleagues out there to recognize that we're doing two very important studies, looking at just ADT and darolutamide versus ADT mono therapy. So, you would say, "Well, how can you do that in the United States?" Well number one, the ARANOTE trial, which is almost completely accrued, is a global, phase three trial, looking at mCSPC patients receiving ADT dero, verus ADT mono therapy, being conducted outside of the United States for equipoise purposes.

I'm also very proud to be the PI of the ARASEC trial, which is a 200 patient, open label study, where our control arm, really interestingly, is from CHAARTED, the monotherapy ADT alone arm with a propensity match scoring evaluation. And this is going to be a really interesting correlate to the ARANOTE. So many of our colleagues are saying, "Well, okay. Triplet, fabulous. It clearly is advantageous. But, what about ADT and dero, that combination? So, we should have results on that fairly soon." So, this is incredibly important. This is a true landmark study, why it was a New England Paper. Matt Smith gave a great presentation at ASCO GU 2022.

Alicia Morgans: Well, I agree. And as we kind of wrap this up, I want to say thank you for certainly including what we have to look forward to, those additional studies are on the way. But in the meantime, we're grateful to have FDA approval, I think, for darolutamide in the setting of ADT and docetaxal. Any closing thoughts from you?

Neal Shore: Yeah. Think about this. This study was started in 2017, and here we are five years later, and despite COVID, we now have 12 life prolonging therapies for advanced prostate cancer patients. We now have clear level one evidence for our mCSPC patients, low and high volume that monotherapy is no longer the standard of care. We have doublets, now triplets. And interestingly in this study, about 86% of the patients were de novo 14% were recurrent mCSPC. And clearly, the benefit was seen in both populations. So for my urology and medical oncology colleagues, radiation oncology colleagues, it's great news for our patients, and so this is a really, really important study that everyone who treats advanced prostate cancer needs to be aware of.

Alicia Morgans: Great. Well thank you so much for your time, and for your expertise.

Neal Shore: Thanks Alicia.