Roundtable Discussion: Participants Consider the Use of Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer

J. Paul Monk, MD (Moderator)

The Ohio State University Comprehensive Cancer Center

The James Cancer Hospital & Solove Research Institute

Columbus, OH

CASE SUMMARY

A man aged 75 years presented with intermittent right hip pain, but his physical examination was unremarkable. Clinical work-up showed that his prostate-specific antigen (PSA) level was at 32.6 ng/mL and his transrectal ultrasonography biopsy Gleason 4 + 4 grade was group 4. Bone scan and abdominal/pelvic CT scan results were negative, and he was given a diagnosis of stage T2N0M0 disease with an ECOG performance score of 1. He was then treated with external beam radiation therapy plus androgen deprivation therapy for 18 months. There was an undetectable PSA level at 6-month follow-up and his testosterone at castrate level was asymptomatic, but 6 months later he developed pain, and his PSA level was back up to 29.4 ng/mL and testosterone levels were at 10 ng/dL. Lesions and a left pelvic lymphadenopathy were identified, and he is now considered to have metastatic disease and be castration resistant.

The patient then started treatment on enzalutamide (Xtandi) at 160 mg by mouth daily and his PSA decreased to a nadir of 3.9 ng/mL 4 months after starting enzalutamide. After 8 months on enzalutamide, the patient had a PSA level of 60.7 ng/mL; abdominal/pelvic CT showed enlargement of known pelvic lymph nodes and bone scan showed progressive disease. The patient was then on docetaxel (Taxotere) at 75 mg/m² intravenously every 3 weeks and daily prednisone 5 mg by mouth every 12 hours. After those 6 cycles, the patient developed bilateral digital neuropathy and docetaxel was held. After 3 months, he had rising PSA and new back pain.

DISCUSSION QUESTION

• What dose of cabazitaxel (Jevtana) would you use at this point in metastatic castration-resistant prostate cancer (mCRPC)?

MAHAJAN: I think 25 mg/m² is a bit too much. I think 20 mg/m² is reasonable to prevent severe myelosuppression.

MONK: Does anyone want to speak for the 25 mg/m²?

BARAI: We realize that many patients don’t tolerate it well, but because this patient is relatively young, it is worthwhile starting at 25 mg/m². And if necessary, use the growth factor, and if still necessary, bring it down in the next cycle.

GHAZAL: I tend to disagree with that. We have a study already, a randomized trial, which showed the 20 mg/m² is just as good in efficacy and much lower toxicity.¹ I don’t know [whether] I would consider the 25 mg/m², because it’s just more toxicity and no extra benefit.

MONK: I’m not sure this is where we would debate it, but I thought [the patient] might have lost a little efficacy. But efficacy is not everything when you’re dealing with toxicity.

MULHERIN: This is not curative therapy. This is very late-line therapy in somebody who’s over 65 years old.

MONK: Fair enough. Will we all agree that growth factors would be used in this setting, either dose? I think we would.

DISCUSSION QUESTIONS

• What are the National Comprehensive Cancer Network (NCCN) guidelines for the use of cabazitaxel in mCRPC?
• How do you select the next line of therapy for a patient with mCRPC who has received docetaxel and an androgen receptor (AR)-targeted therapy?

MONK: [According to the NCCN, they say to,] “consider cabazitaxel and concurrent steroid for patients who are not candidates for docetaxel or intolerant to docetaxel.”² Moreover, cabazitaxel is associated with a lower rate of peripheral neuropathy, especially at 20 mg/m², than docetaxel, and may be appropriate in patients with preexisting peripheral neuropathy.

I agree with that. I’m pleasantly surprised that I don’t see neuropathy worsening. Maybe it’s a selection factor, that they made it through docetaxel and they’re just not going to get it, but I’ve not seen neuropathy. Cabazitaxel is also approved for use in the postdocetaxel second-line setting, and then, either dose can be used, and growth factor should be considered. When you combine carboplatin—because there are data in so-called aggressive variants—you want to lower the cabazitaxel. Does this ring true for everyone?

GHAZAL: Yes, for me.

HUANG: Yes, I agree.

MULHERIN: I agree.

MONK: Would you give cabazitaxel to a patient who did not tolerate docetaxel well? What if the patient had completed greater than 6 cycles—would your recommendation differ? Have you used the combination?

ANWAR: I’ve used carboplatin and cabazitaxel in patients with liver metastatic disease. I see some shortened response, but by that time most of these patients are very refractory. I would still try if they have not tolerated docetaxel well [and] if their disease is progressing.

JABBOUR: Yes, I would use cabazitaxel if the patient did not tolerate docetaxel well. I think it’s a good option, where we don’t have many options, technically. But I did use it before, in [individuals] who did not tolerate docetaxel.

GHAZAL: I agree, and I had the same experience. Again, this is where 20 mg/m² would be even more tolerable than the docetaxel every 3 weeks.

FLEISCHMAN: I was going to ask the moderator: Do you think the interval between the docetaxel and the cabazitaxel makes a difference? Suppose somebody had docetaxel years ago and now they progressed—would you give docetaxel again, or would you switch? Or do you think if it recurs within 6 months, is it going to work?

MONK: That’s provocative, especially in this age of giving docetaxel early in the castration-sensitive setting. It’s been brought up there, where you did not stop docetaxel because of failure, but it was just 6 cycles.

FLEISCHMAN: Exactly what I’m talking about.

MONK: I’ve considered it, but that’s not my routine. So, no; if there’s a long period of time between docetaxel, I usually try docetaxel again. I feel like we have evidence that cabazitaxel works after docetaxel, so trying to get everything in, that’s what I usually do.

FLEISCHMAN: Plus, do we know how it works after 12 cycles of docetaxel, even though it’s split up to 6 and 6?

GHAZAL: We do have some data, years ago, in terms of what we call retreatment with docetaxel, but, again, these were different types of patients.

FLEISCHMAN: What about cabazitaxel after the second round of docetaxel—how well does that work? I don’t know [whether] we know that.

MONK: I don’t know [whether] we know that, either.

MULHERIN: And the cumulative risk for neuropathy if they’ve already had it. If it’s a year later—what if it’s 3 or 4 years later, does that make [a difference]? I have used it again but only if it was a very long time interval in between. Every time I’ve done that, at least in terms of the neuropathy, it was a long discussion with the patient about what they wanted to do. Sometimes it’s driven by other things like co-pays, right? Docetaxel, Part B, all those sorts of things. But I think every time I did that, certainly in terms of the neuropathy, we regretted it; because, as with something like oxaliplatin [Eloxatin], the previous neuropathy, it was still there. So, they were hypersensitive to it. Again, what do you do with neuropathy? You can’t, it’s problematic and there is a role, but you need to think about it carefully.

MONK: One more question on this. How about in your BRCA2-mutant patients? After a PARP inhibitor, would you consider carboplatin-cabazitaxel? I’m just curious about that. [Has anyone had] that experience?

FLEISCHMAN: Giving carboplatin, certainly. I don’t know about the combination.

DISCUSSION QUESTIONS

• How does the sequencing of abiraterone (Zytiga) and enzalutamide affect your treatment plan?
• Where in that sequence do you use cabazitaxel?

FLEISCHMAN: I think when the data look at switching from enzalutamide to abiraterone vs abiraterone to enzalutamide, abiraterone is much worse if you started with enzalutamide, whereas you get a better response if you go from abiraterone to enzalutamide.

In the CARD trial [NCT02485691], was it roughly equal that [individuals] were on abiraterone and then went to enzalutamide, vs enzalutamide to abiraterone?³ In other words, if everybody had been on abiraterone and went to enzalutamide, I don’t think the advantage might be as strong.

MONK: I heard those data as well, and I don’t know [whether] that [information] was available at the start of the CARD trial and whether they stratified [From the Data³]. It was certainly a mixture, so that’s provocative to know whether if you did it one way or the other if it would have been as striking a difference. I don’t think it’s reported out.

FLEISCHMAN: Right.

HUANG: I save the cabazitaxel for later-line use. I realize that when [patients] progress, one after another, and then they get more bone metastases, and they become less tolerable to cabazitaxel, it’s probably better to use—the data do show it’s better than the other, the AR-signaling agent.³ But I’m thinking [that] for tolerability purposes, we probably should consider using cabazitaxel earlier.

MONK: Any other opinions on that?

GHAZAL: The fact is we have survival advantage proven in a randomized trial, but mind you, the entry criteria, these are PSA doubling times on the lower side. You can argue, [individuals] who have PSA doubling time more than a year or who had prolonged response to, let’s say, abiraterone—those do not fit exactly the CARD entry criteria. But most of our patients fall in the CARD entry criteria, so changing mechanism of action is a better strategy to prolong life in these patients, [rather] than going to another AR agent.

FLEISCHMAN: How many [individuals] who went from abiraterone to enzalutamide or enzalutamide to abiraterone ended up later getting cabazitaxel? Probably none of them. They’re not dead necessarily, so is it clear that they couldn’t have gone on to cross over to the other arm?

MONK: Crossover was allowed, and I do think post–clinical trial therapy did include individuals who went on to either arm. So, no; I do think there was a mixture of subsequent therapies involved. That prior point, I think that’s something I follow. I have occasional patients who are on abiraterone or enzalutamide for 3-plus years. I think the record in my clinic is 6 years. So that’s unusual, but that does seem to suggest that in changing from abiraterone to enzalutamide, you might get some mileage out of this—unusual patient, but that’s anecdotal. I certainly don’t think we have any data to suggest that we know that for sure.

FLEISCHMAN: You’re saying that somebody got 6 years from enzalutamide after failing abiraterone?

MONK: No, the front line. Front line, they got a long benefit.

FLEISCHMAN: But when I switch, I usually get 4 to 6 months at best.

MONK: That’s my experience, too. It’s short; 1 scan, maybe.

FLEISCHMAN: It’s short, and if you go from enzalutamide to abiraterone it’s even worse, in my opinion.

GHAZAL: I heard an explanation one time. I don’t know [whether] that’s about pharmacokinetics of abiraterone use after enzalutamide, that the enzalutamide doesn’t get out of your system quickly and it can interfere with the abiraterone dose in your bloodstream. That may be an explanation for why giving abiraterone after enzalutamide may take a month before you get to a level where you really have an effective dose of abiraterone. That’s 1 explanation why that sequence didn’t seem to work as well.

MAHAJAN: My impression is that that is a settled issue; like if you have used 1, there’s no point trying any of the other 4.

GHAZAL: It’s a different mechanism of action, obviously. The 2 drugs are not the same.

MAHAJAN: We have radioactive therapy as well, the lutetium [¹⁷⁷Lu-PSMA-617; Pluvicto]. Then also we have more data with cabazitaxel.

MULHERIN: I’d also point out that despite this, cabazitaxel is chemotherapy; it’s going to be less well tolerated than another hormonal agent for most patients, regardless of which one you’re looking at. Since these data were released, yes, I practice based on this. If somebody is very elderly and frail, obviously there are some patients you’re just not going to want to give chemotherapy to.

So, some patients…you don’t like it, but you may end up putting them on another hormonal agent, regardless of what the data show. They’re just not going to be candidates. It doesn’t mean that that strategy is dead, but assuming they are candidates for it, yes. I think for most patients, yes, I agree, I’d move on to cabazitaxel. Most patients with mCRPC are not 50-year-old marathon runners; they’re older than that, and they have other comorbidities.

MONK: Is anyone ordering AR-V7 [androgen receptor splice variant V7]? Does anyone find that useful?

GHAZAL: Initially I was ordering when it first came out, but when the follow-up data showed there was not a good correlation with what’s happening clinically, I stopped doing it. It has ups and downs.

MONK: I haven’t ordered it in years. I find that if I even do it, I follow the PSA even though PSA is problematic. I don’t find AR-V7 that useful.

DISCUSSION QUESTION

• Where do you see cabazitaxel and ¹⁷⁷Lu-PSMA-617 fitting into the treatment landscape for mCRPC?

MONK: For eligible patients, what factor would influence your use of ¹⁷⁷Lu-PSMA-617? Liver/lung involvement, high volume/rapid progressing? Are there specific groups or types of patients who you would not want to refer for this imaging or use of ¹⁷⁷Lu-PSMA-617? Where do you envision these therapeutics fitting into the treatment landscape for mCRPC: cabazitaxel vs ¹⁷⁷Lu-PSMA-617?

SHAH: For rapidly progressing patients, I prefer the cabazitaxel and carboplatin.

MONK: Any other thoughts on these points?

GHAZAL: No, I agree. Access obviously is a problem, so you may end up doing cabazitaxel anyway because of the poor access we have had so far to the actual treatment. I realized in our center we needed a specific license for this specific radioactive compound, and that takes time as well. With the access problem, I think most [individuals] are obviously using cabazitaxel first.

In competition in this line, a PARP inhibitor would also be in this line of therapy competing with both ¹⁷⁷Lu-PSMA-617 or cabazitaxel, especially with the newer data from the PROpel trial [NCT03732820] combining PARP with abiraterone or enzalutamide.⁴ Again, provocative data, especially in BRCA wild type. PARPs are here to stay, and we need to also include them if you want a complete discussion about how you sequence these agents, because this is where PARP can also fit in.

_REFERENCES

_{1. Eisenberger M, Hardy-Bessard AC, Kim CS, et al. Phase III study comparing a reduced dose of cabazitaxel (20 mg/m2) and the currently approved dose (25 mg/m2) in postdocetaxel patients with metastatic castration-resistant prostate cancer-PROSELICA. J Clin Oncol. 2017;35(28):3198-3206. doi:10.1200/JCO.2016.72.1076}

_{2. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 4.2022. Accessed July 12, 2022. https://bit.ly/3hNIIrw}

_{3. de Wit R, de Bono J, Sternberg CN, et al; CARD Investigators. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med. 2019 Dec 26;381(26):2506-2518. doi: 10.1056/NEJMoa1911206}

_{4. Saad F, Armstrong AJ, Thiery-Vuillemin A, et al. PROpel: phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2022;40(suppl 6):11. doi:10.1200/JCO.2022.40.6_suppl.011}