Case 2: Challenges Treating CSPC With Visceral Metastases

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Jorge Garcia, MD:Ken, I thought that visceral patients needed to get chemotherapy, and I think LATITUDE proves me wrong. If you look at the patient makeup for LATITUDE, roughly 14 and 17 against CHAARTED had high-volume disease by virtue of visceral disease. Do you really think that visceral disease is what most people are seeing right now, and should it be utilized to define chemotherapy?

Kenneth Kernen, MD:That’s a great question, and that’s what Alicia was talking about earlier. I think this is where this whole shared decision making comes in. To Neal’s point, if they’re younger, I do think they tolerate it well. And for me, I think, “OK, if it’s me, I’m a younger guy. If this is my level of disease, I’m going to probably do that.” So I’m going to recommend that. But I do think if they sort themselves out for various reasons—they can’t tolerate it, or it’s financially unacceptable because they have to take time off from work—then I think I would move them toward AR [androgen receptor] therapy. But for the most part, I agree. If they’re younger and they can tolerate it, I would move to 6 cycles of docetaxel first.

Jorge Garcia, MD:That’s interesting.

Kenneth Kernen, MD:Even though, as you said, the data are a little bit...

Jorge Garcia, MD:I don’t think we’re going to be able to compare across trials. It’s intriguing. I was part of the ECOG data. As of June 2017, I moved completely away from chemotherapy to oral therapy, which brings up the point: Are there any absolute contraindications, medical ones, for which you should say, “Maybe I’ll do chemotherapy instead of an AR inhibitor or another inhibitor?”

Neal Shore, MD, FACS:What if you’re concerned that the patient has a poorly differentiated neuroendocrine tumor, visceral metastasis, low PSA [prostate-specific antigen], lytic bone lesions? Are you going with an AR inhibitor, or are you going to go with a taxane, possibly a carboplatin combination?

Jorge Garcia, MD:That’s a great point. If I know that the patient has significant neuroendocrine differentiation of small cell component, my approach is not an oral agent. My approach is chemotherapy. When I’m selecting cytotoxic-based chemotherapy, I would probably just start on a carboplatin-based approach or a platinum-based approach.

The bigger question right now for us would be, do you use carboplatin-etoposide, typically with the small cell phenotype, or do you do a carboplatin-taxane? We finally have the publication from Ana Aparicio and Paul Corn of what we define as the The University of Texas MD Anderson Cancer Center regimen of carboplatin-cabazitaxel for those patients with AR-null disease. I oftentimes don’t do carboplatin-cabazitaxel up front. I’d probably choose carboplatin-docetaxel, so I can reserve cabazitaxel for later. But I have to know that they have a neuroendocrine phenotype before I do that. Alicia, would you?

Alicia Morgans, MD:I agree with you completely, and I think it’s always important to talk with a pathologist if that’s what you think that you’re seeing. Synaptophysin can be expressed in adenocarcinomas, and sometimes it gets tricky because they’ll report, “Oh, it’s staining the synaptophysin,” but they’re not actually saying neuroendocrine differentiation. And so those conversations become really important.

But just to get back to your other question, is there something about a patient that would completely be a contraindication that’s medical and not a financial toxicity, which I end up seeing relatively commonly? You know, a malabsorption disorder—if they can’t take a pill and have it be absorbed, perhaps? Or maybe a seizure disorder? We can talk about that and the data again if you want. Or maybe severe liver toxicity, though of course they’re not going to be able to take docetaxel then either. Maybe that’s an ADT [androgen deprivation therapy]—alone patient. But I’d throw that back at you. Are there other commonly seen medical issues? None of these are common, just to put that out there.

Jorge Garcia, MD:You are right. I don’t think there is an absolute contraindication from any of the oral agents, in my personal opinion. I think my concern is, for instance, if we have an obese male, a cardiopath with CHF [congestive heart failure], CAD [coronary artery disease], significant issues with hypertension. I think those patients may do better if they go quickly to docetaxel, right? This is because of the chronicity of an AR inhibitor, right? We think about the greater risk for cardiovascular morbidity and toxicity. And I have done it lately, but they’re not that common, right? I don’t know if you feel the same way.

Neal Shore, MD, FACS:I completely agree with you. If you’ve got somebody who’s got fluid retention issues or heart failure issues, yes. With abiraterone, even at 5 mg, let alone 5 mg twice a day, the chronicity of that could be a real issue. But it’s interesting. You brought up earlier this whole notion about the concomitant that we saw—about 40%, 45% in ENZAMET. But yet in ARCHES we saw that the 11%, or maybe it was 18% in both arms who had docetaxel beforehand, if you look at the forest plots, they did better regardless of high volume [or] low volume, in terms of the rPFS [radiographic progression-free survival] primary endpoint.

Jorge Garcia, MD:Right.

Neal Shore, MD, FACS:And we published that. What’s interesting to me is enzalutamide is a CYP4A enzyme inducer, and docetaxel is also metabolized through CYP. Earlier, when we were talking about that earlier case, you were talking about the whole notion of drug-drug interactions. This is where we need to start to think about, whether it’s apalutamide or darolutamide, how that could have an effect on the metabolism of docetaxel. I don’t know. It still gives me some optimism for the ARASENS trial.

Alicia Morgans, MD:I agree. I think it’s important. At least in my practice, I’m not using triple therapy at this point. I think the ENZAMET data suggested—we have to remember it was concomitant use of docetaxel and enzalutamide. And perhaps because of this issue of the metabolism being through that same CYP enzyme, there was actually a higher rate of toxicity in the triple therapy arm. Interestingly, the docetaxel toxicities that we saw kind of amplified in that trial. So I’m definitely not using them concomitantly. I’ve tried to not do sequential until we get to metastatic castration-resistant prostate cancer, just because I don’t know the answer yet. I am definitely looking forward to ARASENS. But I think PEACE-I will help us understand this too, which is also looking at some of these combinations to help sort things out.

Transcript edited for clarity.