Alicia Morgans: Hi, I'm delighted to have here with me today, a friend and urologist, Dr. Neal Shore, who is at the Carolina Urologic Research Center in Myrtle Beach. Wonderful to have you here.

Neal Shore: Thanks, Alicia.

Alicia Morgans: Wonderful. I wanted to talk to you about your impression of the clinical implications of the CARD trial because I think this Phase IV study that was recently reported, published in the New England Journal, really demonstrating the first third-line treatment for metastatic CRPC, that prolonged survival for cabazitaxel as compared to treatment with an alternative AR targeted agent in men who had had chemotherapy and the other AR targeted agent in their prior treatment history, was really a practice-changing and very informative study. And I wanted to get your thoughts on this trial.

Neal Shore: Yeah, I think it really was important and congratulations to Ron de Wit and the team that got that across 255 patients, which at face value, some may think, okay that's not a huge trial, but it really, it was, New England Journal worthy. And I think really what it shows is that something that happens very commonly in real world practice is we have oral agents such as abiraterone and enzalutamide, which is what CARD looked at, were given either for 12 months or less prior to docetaxel or 12 months or less after docetaxel. And then whichever one the patient received, abi or enza, patients were randomized upon progression to receiving a cabazitaxel versus the other oral, novel hormonal agent.

And what the data really nicely shows is the rPFS and the OS benefit of receiving cabazitaxel. And I think for many of our colleagues, urologists and medical oncologists, there's always been sort of a more comfort level of saying, "Well, I've got one oral agent, I'll just go to the other." Maybe it's for simplicity purposes, maybe there are other issues involved, maybe there's a perception of intolerability. But in my own personal experience and now kind of amplified by CARD and we saw some other studies too, like the really nice trial of the PLATO, led by Kim Chi, that once again the switch going from one oral androgen receptor access targeted therapy to the other tends to be a lateral move. And so cabazitaxel, with its own unique mechanism of action, clearly beneficial post docetaxel is really the way to go.

And so I think that we shouldn't be picking that switch therapy because it's just oral agent and it's easier to do and maybe more appealing to patients. But now we have really level one evidence that cabazitaxel is really more beneficial. I think that's really the take home. I think that our urology, oncology colleagues and medical oncologists in the community who see these patients and take care of these patients really need to review this data. Because when you get something that both shows statistically significant rPFS and OS benefit, it's hard to not recognize that.

Alicia Morgans: Absolutely. And what I think is really interesting is that I think in the field we generally have had concerns about the tolerability of chemotherapy and what we saw in the CARD data when we look at the adverse event profile is that there were similar adverse events, maybe slightly more chemotherapy-related in the cabazitaxel, of course, but the grade five events related to treatment were actually higher in the AR targeted agents and when we saw the patient-reported outcome data, which was actually recently presented at GU ASCO, we found that patient-reported outcomes, so what the patient actually reports back as their quality of life was better in the cabazitaxel arm than in the AR targeted agent arm.

And that started from the very beginning that patients actually had an improvement in quality of life on cabazitaxel and a decline in quality of life on an AR targeted agent likely because the AR targeted agent is not working and we're watching symptoms related to cancer progression plus whatever toxicities the agents have that we've just put this patient on. And so it makes a lot of sense from my perspective if we listen to the patients telling us how they're feeling, that it's not more difficult to tolerate.

Neal Shore: Excellent point. It's all in the New England paper and you're absolutely right. And I think a big part of it is, especially as we've moved towards understanding the enhanced role for taxane-based therapies , metastatic hormone-sensitive patients, to mCRPC, especially for patients who start on AR targeted therapies and mHSPC, the really robust role for taxane-based therapy in the mCRPC population. And to your point, a drug such as cabazitaxel has, it's a consistent safety profile. What we saw in CARD is this consistent safety profile or what we saw in the PROSELICA trial as well as what was seen in the pathway approval trial, known as the TROPIC.

And one of the things I particularly like is, there's a lot less neuropathy that we've seen with docetaxel and that was consistent as well. I think your points are really well taken. A big part of it I think is still, there's the verbiage of saying chemotherapy, but this is actually really a more active treatment arm compared to the switch that's clearly demonstrated in the CARD data. I think it's really one of the most important pieces of data that came out of ESMO.

Alicia Morgans: I agree. The other thing that, just to really piggyback on this as a comparator to docetaxel, when we looked at a lower dose of cabazitaxel, which is actually what we use in the US typically is 20 milligrams per meter squared. That may be even more tolerable than what was used in the CARD study, which was 25 milligrams per meter squared.

Neal Shore: Absolutely, right. Right.

Alicia Morgans: In the US we often start with that dose. We can increase that dose if patients find it really easy to tolerate to try to see if we can get a little additional disease benefit or anti-disease benefit. But we in the US may actually even have better tolerability if we're using that dose that is now guideline recommended for us.

Neal Shore: Yeah, yeah, agreed.

Alicia Morgans: Absolutely. The final thing I wanted to mention is that SREs also appeared to be lower in those patients treated with again an active agent, cabazitaxel as compared to this again, second AR targeted agent and then really just to emphasize once more what you've said that other studies, the control arm of other studies including the PROfound trial, a Phase III trial of men who had multiple prior treatments including AR targeted agents and docetaxel chemotherapy, who are randomized to olaparib versus the other AR targeted agent have shown us a very, very similar futility essentially to this back-to-back AR sequencing. And just to mention it's not just back-to-back. It could be sandwiched as well, which was a another subgroup analysis within CARD, sandwiching does not restore the potency or the effectiveness of the AR agent.

Neal Shore: Absolutely.

Alicia Morgans: Great. Well if you had to give one real final message, and I know you've given multiple messages throughout this, what would it be to clinicians who are trying to think about how do I use the CARD data in my daily practice? Is it worth it for my patients?

Neal Shore: Yeah. I would say to my urologic colleagues who have an advanced prostate cancer clinic or our busy community medical oncology colleagues who are not necessarily in the throes of all the trial data and understandably, they're taking care of large volumes of patients, is that, think about clearly look at the evidence based upon the CARD trial, based upon PLATO, based upon PROfound as well and really strongly think about moving cabazitaxel up earlier, especially after a patient's failed one of the AR targeted therapies and has also received docetaxel.

Alicia Morgans: Absolutely. I 100% agree. I think as we think about what's important to patients, whether it's living longer or feeling better, actually both of those endpoints were met in the CARD trial in third-line after docetaxel and one of the AR agents as compared to the other. It's important for us to give this opportunity to patients and use all of the tools that we have at our disposal. I appreciate your time and your expertise. Thank you so much.

Neal Shore: Pleasure.