Alicia Morgans: Hi, this is Alicia Morgans GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, Dr. Stephen Freedland, who is a Professor of Urology at Cedar Sinai in Los Angeles and Dr. William Oh, who is the Chief of the Division of Hematology and Oncology at Mount Sinai in New York. Thank you so much for being here with me today, both of you.

Stephen Freedland: Hi, Alicia.

William Oh: Great to be here, thanks.

Alicia Morgans: Wonderful. So I wanted to talk with you guys a little bit about one of the presentations at ASCO 2020, the virtual meeting, there was an analysis of the CARD data, the cabazitaxel data in metastatic CRPC patients in the third-line, that was really looking a little bit more closely at the differences that may exist or may not exist between elderly patients and patients who were less than elderly. The cutoff in this particular analysis was greater than or less than 70 years of age. And I'm wondering if you could tell me a little bit about this analysis, Dr. Oh, and what your thoughts were top level.

William Oh: Sure. So obviously chemotherapy has been and remains a very important treatment for metastatic CRPC patients. And the CARD study was a randomized trial looking at men who received docetaxel with mCRPC and also received first-line AR targeted therapy, either abi or enza. They were randomly assigned to receive cabazitaxel or the opposite AR targeted therapy. So this is third-line treatment, and many of these patients actually remained quite intact. They were randomly assigned to one or the other, and it was significant survival and PFS benefit in the men who received cabazitaxel compared to the opposite AR targeted therapy. And we saw this data last year, and it was published in the New England Journal of Medicine because it was such an impactful and important study.

So the data in this abstract and presentation at ASCO in 2020 is really to look at older patients, patients older or younger than the age of 70. And one of the reasons to look at this subset is that we all know that men with prostate cancer are older, and we know that older men are at greater risk for side effects, particularly of drugs like chemotherapy. And I think in my career, and I think for you, and for all of us in this field, there's always been a concern that men who are older will not tolerate chemotherapy. And this is an important question. This was a subgroup analysis based stratified by age, over 70 versus under 70. And basically the top-line result was that there was no difference in the PFS, the rPFS, or the OS benefit based on an older or younger age.

Alicia Morgans: Great, thank you. And these are really important conversations. As you mentioned. There's definitely some thought in the field that these drugs, like cabazitaxel, taxane chemotherapies may be more challenging to give in an older population. Importantly and interestingly, the benefit seems similar. And also importantly and interestingly I think, the CARD data was done using a dose of cabazitaxel that's actually a little higher than the one that we typically use here in the U.S. In that study, they use 25 milligrams per meter squared whereas we usually use 20 milligrams per meter squared. And then most of us still are many of us still use Neulasta®. It was definitely used in the CARD trial. And so when you're thinking about these kinds of decisions, Steve, I know as a urologist, you may be more peripherally involved in these kinds of decisions. What do you think about data like this, looking at differences in populations if they exist or not as we're using that and the way that we use that information to make treatment choices?

Stephen Freedland: I think these are very important data for sure. And I think there's this perception out there that, a novel hormonal agent abi or enza, it's easier, it's kindlier, gentler and response rates when you failed one going on to another aren't zero. And so, therefore, "Look, let's just give it a try. It's not that toxic. Let's just see what happens." So then I think these are important data that when you're sitting with the patients, "Yeah, no" as a urologist not giving chemo, but we are having those conversations in terms of what the patients to say, "Look, I'm older. I don't really want it. I've been through chemo once and I'm not excited about going through it again" and, "Oh, let's just do the other one." I think it's important to remind people that first off when you look at the toxicity profile in the AEs, you're right. This is a higher dose of cabazitaxel than typically given.

They weren't dramatically different between the two. So it's not like cabazitaxel had all of these toxicities and other hormonal agents had zero. The numbers actually aren't that dissimilar. And you actually, particularly in older men, saw an increased risk of cardiac disease with the novel hormonal agents in the older patients. So something that, yes, we tend to think older, frailer, maybe not great for chemo, but they have cardiac issues and the alternatives are not great for cardiac reasons. So I think a lot of it comes down to fitness comorbidities, overall things, and not necessarily age as a strict number, which we know intuitively in earlier stage disease, but we often tend to forget and go by age. So it's really looking at the patient. Not just a single number.

Alicia Morgans: I completely agree. And thank you so much for highlighting the AE issues. So it was really interesting I thought that the incidents of febrile neutropenia as we would expect was higher with cabazitaxel as was diarrhea, but cardiovascular AEs were actually higher in AR targeted agents than in the chemotherapy arm. William, does this affect your treatment conversations with patients having this piece of information for them?

William Oh: Well, I think it's very important to customize your treatment plan for each patient. We've appreciated recently that there are important toxicities related to AR targeted therapies. They're terrific drugs, but for example, we do understand that there's more cardiovascular risk with drugs, for example, like abiraterone with prednisone. And you see, outside in this randomized trial as Steve the pointed out, these were grade 3/4 toxicities, not just small and inconsequential rises in blood pressure. These were serious AEs.

That said, obviously, there are people for example, who are not great candidates for chemotherapy, and you pointed out something really important in this study, which is the dosing issue. Most oncologists would not use 25 milligrams per meter squared, which is what was used in this randomized trial. At the time it was the labeled indication. But we realized from subsequent studies afterward that 20 milligrams per meter squared would be perfectly reasonable and as efficacious as 25. So that's what most oncologists in the United States are using. That's what I use. There are times when if I think that a patient might be frail because of his age, I might start at a slightly lower dose, but in most patients, I found that they tolerate 20 milligrams per meter squared quite well. And I think that customization to the situation at hand is really, really important, but the most important thing about this study and the most important take-home messages, giving drugs, because they're easier, or you think they're easier that don't work is not a good strategy.

Bad drugs don't help patients and these are great drugs when you use first-line. But we know from many, many other studies that when you use them that ... Even if you flip over to the other drug from abi to enza and enza to abi second-line, certainly third-line fourth-line in mCRPC, these drugs do not have activity that justifies their continued use and study after study keeps showing that this study clearly shows that second-line chemo is much more valuable than second-line AR targeted therapy, at least in the confines of this trial.

Alicia Morgans: Yeah, just to emphasize that again... An active treatment, particularly one that's tolerable, and this seemed to be tolerable even at this higher dose is going to be more effective for your patient than a drug that the patient probably already has a resistance mechanism against. So AR followed by AR, even if you have a docetaxel treatment in the middle and you think, "Oh, this sandwich approach is going to be better and restore sensitivity," it's not an effective strategy. And I think it's interesting too, that we saw this, not just in CARD. We actually saw this in PROfound as well. So these were patients who had AR targeted therapy, docetaxel, they may have actually even had cabazitaxel, and when we randomize them to an agent that had happened to be quite effective, a PARP inhibitor, versus the second AR targeted agent, we actually saw very similar control arm as we did in the CARD trial. And that population wasn't even restricted to a population that had to have disease progression on an AR targeted therapy within 12 months.

So I don't think that this story is unique to this group of patients who progressed within 12 months. It's probably that as you develop resistance to an AR targeted approach, you have developed resistance and another drug with the similar mechanism of action's not going to work. And so I really appreciate you bringing that out. You know, Steve, when you're seeing patients, you actually work at a veteran's hospital, and certainly nothing you say in terms of treatment conversations would be a recommendation from the VA. But just to comment, as you're treating patients in that facility, I can imagine particularly if they have many comorbid illnesses that it would be maybe not uncommon as for any practice that includes patients with many comorbidities to say, "Well, I'll give them the easy way out." As we just discussed, that does not seem like the way that we'd want to go with the CARD data come into your conversations, if you were having them with patients in your practice, particularly this geriatric data.

Stephen Freedland: Yeah, I know. Absolutely. Again, this is third-line therapy we're talking here. And so the number one threat in that stage to quality of life is the cancer. It's not the treatment. It's progressing cancer. These patients, even with good therapy, don't have forever to live. They're worried about pain from the cancer and those issues. And so even if you have an agent that is a little bit higher risk of AEs, and we see that a little bit higher risk, but it's modest risk, but we saw data from GU ASCO, for example, in February that actually showed cabazitaxel had a better quality of life. And so to me, the primary thing is we got to get good cancer control. We're beyond the stage of subtle differences in AEs.

You've got to get to an active agent and these novel hormonal agents, second novel hormonal agents just are not active enough. And age, again, says here is a number to be thought of. And it does impact counseling in terms of AEs and things to think about. But patients did really well. And it was actually over half the patients and an entire study were over the age of 70.

So it was over 50% of these patients and they tolerated it well. Now, these are ECOG 0/1. So if you had an ECOG, 3 or 4 patients who are 75 and 80, harder to know, but for that healthy kind of chemo fit patient, just because they're over 70 shouldn't matter.

Alicia Morgans: Great. Well, as we wrap up, Dr. Oh, what are your closing thoughts and messages to the listeners?

William Oh: I think the most important thing is, think of what's best for your patient. And don't use age cutoffs as a reason not to use or to use a certain treatment. I've given chemotherapy to men in their 90s. If they're fit and you're able to manage the side effect risk and you individualize it, there's really no upper age limit for how chemotherapy can help if you're able to really be an experienced oncologist and deliver the therapy effectively. And as Steve said, and as we all agree, you have to be able to give your patients the best shot at controlling the cancer. Cause in the end you know mCRPC is still lethal.

Alicia Morgans: Absolutely. And any closing thoughts, you've given us lots to chew on, Dr. Freedland, any closing thoughts from you?

Stephen Freedland: Yeah, no. I mean, I think William said a very nice thing. I think to have that conversation with the patients and to let them know we have treatment options that can keep the cancer under better control, prolong survival, prevent pain, improve quality of life, and to present them with the options and not deny them life-prolonging therapies just because they happen to be a particular age.

Alicia Morgans: Absolutely. Well, thank you both for your review of this information. We of course thank the CARD investigators for doing this analysis so that we understand best how these treatments may affect our older patients. And I appreciate your time today, both of you.

William Oh: Thank you.

Stephen Freedland: Thanks for having us.