Roundtable Discussion: Aghalar and Vaena Look at The role of Cabazitaxel in CRPC

Jahan Aghalar, MD (Comoderator)

Hematologist/Medical Oncologist

New York Cancer & Blood Specialists

New Hyde Park, NY

Daniel Vaena, MD (Comoderator)

Hematologist/Medical Oncologist

West Cancer Center & Research Institute

Germantown, TN

PARIKH: The patient received standard-of-care treatment, so I don’t know what anybody else would do, unless you enroll [him] in a trial. There are some new data coming out with some of the oral drugs that we can add on, but [this patient is] not considered high risk if he only [has] T2 [disease].

AGHALAR: He doesn’t have any evidence of local advancement, but he does have a high glycine score; but as of now, with the novel androgen-directed oral agents there’s no role for using those. Now that we see he has evidence of bone metastasis, at least 2 of them seen on the right hip, would anybody recommend the addition of an osteoclast-targeting agent such as denosumab [Xgeva]?

PARIKH: Yes.

AGHALAR: With castrate-resistant disease, right? So let’s say this was a patient that had a castrate-sensitive metastatic prostate cancer: would anybody use an osteoclast-targeting agent in that context? [Would] anybody not use denosumab in the castrate-sensitive disease?

MUSHTAQ: Well, not in castration-sensitive [disease] because there is no benefit in using antitherapy in castration-sensitive disease.

AGHALAR: I think previously, there had never been any benefit shown with zoledronic acid [Reclast]. In terms of the uses of denosumab, to date, there are no data to support any benefit. I know that out there in the community, a lot of times it is being utilized. Now, it would be something that I would personally avoid with these patients with prostate cancer. We’re looking at treating them for 5 to even 10 years with metastatic disease, so the risks of osteonecrosis of the drug go up with cumulative exposure to these agents, so I would agree that it would be best…to treat these patients once they reach the castrate-resistant setting, as was pointed out.

PRASAD: This patient may get metastatic disease, but if he had extensive bone metastasis and is castrate sensitive, would you consider a bone agent?

AGHALAR: Personally, in my practice, I do still wait until castrate resistance, even if a patient has widespread metastatic disease. You have to expect that they are going to have good disease control with androgen deprivation therapy plus or minus chemotherapy, so the risk for pathologic fractures in the castrate-sensitive setting is much lower. As of now, [there is] no evidence to support doing it and…no evidence to say that it’s detrimental to do that, but in my practice, I wait until castrate resistance.

SAEZ: Another issue to consider is to make sure what the bone health of the patient is, because you’re going to put them on luteinizing hormone-releasing hormone [LHRH]. …Had this patient developed bone loss, [it would be prudent to] use that, at least from the standpoint [of preserving] bone health in some of these patients.

AGHALAR: We know that abiraterone plus prednisone utilized prior to chemotherapy does have an overall survival [OS] benefit compared with chemotherapy, based on [results from] the COU-AA-302 trial [NCT00887198].¹ [It’s the] same thing with enzalutamide, [which] also has an OS benefit in the prechemotherapy setting, based on [findings from] the PREVAIL trial [NCT01212991].² In terms of docetaxel, I would also agree [that] it would not necessarily be the optimal choice; of course, sometimes there may be considerations to use docetaxel if there are patients that can’t afford the co-pays for these expensive oral agents, so that may be a context where you may want to use docetaxel. At the same time, many will also still argue that [with] abiraterone [Zytiga] or enzalutamide [Xtandi] prior to chemotherapy, you can still achieve a good, robust response. Would anybody ever consider sipuleucel-T [Provenge] in this context?

PARIKH: There are data out there saying that sipuleucel-T does work. So if it’s the ideal patient with minimal disease and it leaves you all the other options, [then it might be appropriate to use].

AGHALAR: In the metastatic castrate-resistant setting, there are some OS data to support it. You’re not going to get a robust response with sipuleucel-T, but that would be perfectly defensible. [Is there] anybody who would choose radium-223 [Xofiigo]?

PARIKH: I think I would consider it, but I don’t know why you wouldn’t consider it.

AGHALAR: [Using] radium-223, a bone-targeting agent… with alpha particle–directed radiation also has shown an OS benefit. Right now, the FDA-labeled indication is for patients that have symptomatic bone metastases; this was a patient that did have some symptomatic bone metastases, so that would also be another defensible choice.³

PARIKH: My question is, do you commit to the full 6 months even if the PSA [level] goes up during the treatment.

AGHALAR: In my practice, I would keep an eye on the PSA, but if they are not having evidence of symptomatic progression, then I would try to get through the full 6 months.

VAENA: I would do the same. The PSA typically goes up with treatment and it is not a surrogate for response with radium-223, to my knowledge. Once you decide to start [treatment with this drug,] I would finish the 6 months.

SAEZ: If a patient had significant visceral disease or bone disease and were young, I would consider chemotherapy in that setting, but for the most part, I use AR-targeted agents.

AGHALAR: It’s a point well taken. There are very limited data to support efficacy for patients with visceral disease in AR-directed therapy. Not to say that it’s not useful, but I would agree, chemotherapy would be something to consider in that context.

AMBIKA: What do you think about the PEACE1 trial data [NCT01957436]? Are they something which you’ll consider in a young patient?

AGHALAR: That’s the age-old question as to whether frontloading your therapeutic options is the better way to go as opposed to sequencing your options. As of now, we have to see whether or not there’s any OS benefit in doing so, but [it’s] something to look out for to see what the long-term results would show. But in my practice, I wouldn’t be combining chemotherapy with any of the AR-targeted agents.

PRASAD: [For this patient,] I chose cabazitaxel [Jevtana] because there are data to show that after docetaxel, patients do respond, and I have had a few patients like that who responded and of course do not have any actionable mutations. We don’t have any specific targeted agent, and we can’t do immunotherapy.

MUSHTAQ: So the reason for choosing cabazitaxel would be his performance score and progression on enzalutamide in the past, and docetaxel, and [that he is] castration-resistant. Though would [that] be the option for choosing cabazitaxel in this patient?

AGHALAR: Let’s say this patient was concerned about toxicities. I mean, he [had] already developed some significant neuropathy with the docetaxel and he had fears of further toxicities. Would anybody shy away from chemotherapy for that reason?

PARIKH: I would. I think quality of life is very important and especially in this patient population because we’re just buying time, essentially. And if he doesn’t want to have additional toxicity, why not use olaparib [Lynparza] or maybe even a clinical trial here?

AGHALAR: I think once we get into the third-line castrate-resistant setting, quality of life becomes more and more of a priority, as it is from the beginning, but more so as we reach later stages of the disease.

AMBIKA: I think we have data from the CARD trial [NCT02485691] saying that cabazitaxel is better.⁴ …We all know that, but [the] point is well taken about the performance status and quality of life.

VAENA: I think the challenge with these data [is that] I see a lot of other physicians practicing with data from the CARD trial that reflect patients who had [received] prior docetaxel. What we actually see in practice—at least I see this a lot in practice—are…patients who get the first-line AR inhibitor for CRPC as an example, and then they…get abiraterone and then they switch over to enzalutamide. That’s where the CARD data, for instance, are not even applicable to that situation, where patients are switching from one hormone agent to the other. The data are compelling, but [they are] data for patients who had prior docetaxel [and are] just not reflective of most patients that I see [on] the referral basis.

As an example, in my practice, I use these data to suggest that, yes, switching to chemotherapy is better than switching to the second AR inhibitor, just because the response rate for the second AR inhibitor is much lower. But that’s just not what these data are.…If I have a patient…getting first-line abiraterone or enzalutamide, and their disease is progressing but [they are] reluctant to start docetaxel chemotherapy, we suggest that switching to chemotherapy is better. But again, it’s not this perfect scenario.

The other thing that I use is ARV7, where certainly, if they are positive for ARV7, it’s a strong reason not to use [the other hormone agent]. But I was curious to hear from you all if these data are applicable to how you practice or not, because that’s not what I see people doing.

AMBIKA: I think if you strictly follow data, you’re not supposed to switch from enzalutamide to abiraterone because the data are saying it doesn’t do anything. There may be a 30% response rate, so if somebody started on enzalutamide, the second line should be chemotherapy rather than switching to abiraterone, even though we all agree that’s not what we see in the real world.

VAENA: The data for chemotherapy also, for that initial chemotherapy switch, are…very limited.

AGHALAR: Any specific approach in managing toxicities? The one thing I wanted to point out is that the dosage of cabazitaxel that was used in this trial was 25 mg/m². That was the dosage that was used at the initial FDA approval for cabazitaxel. A couple of years later, the PROSELICA trial [NCT01308580] data driven from Johns Hopkins [University] showed a lower dosage of cabazitaxel, at 20 mg/m², has equal efficacy but has significantly decreased toxicity.⁵

AMBIKA: I think the bone matter suppression is a concern. There is some thought [about doing] it after cabazitaxel so that the count will be a little bit more preserved, but I think the therapy trial has shown this may be better than cabazitaxel, so it’ll be interesting to see how this shakes out.

I think that dry mouth is also a concern if somebody has long-term survival. That’s [to do with] quality of life [and there’s] around 40% incidence of dry mouth.

AGHALAR: That was seen at a high rate. [Does] anybody foresee the PSA imaging as part of the screening to be a potential barrier in using this agent in the future?

PARIKH: If we can get the insurance providers to pay for it, I mean, that’s the right [thing to do]. Right now, if I try and order it, it’s considered “experimental” by everyone except Medicare. Our group was part of the trial set that did this.

PRASAD: This is kind of good scientific rationale, you know, and especially in the [patients with] CRPC, if we don’t have any other options. I think it’s good, and the results are good too, and the data from the trial.

VAENA: I think the challenge from this trial is that these patients are very advanced, and they had prior hormones and prior chemotherapy, so it’s a patient population that didn’t have a lot of options. If you look [at it] from that standpoint, you had a very effective and certainly a positive trial so certainly [its data offer] another tool to use, but we didn’t understand from this trial what was going to be the best sequence. The way this trial was done is basically very late line for patients that had no other options, and that’s a challenge that I see for understanding where this treatment fits.

SAEZ: I think you’re going to have practical issues. All these drugs that are radionuclides, there are very few centers around that have access to that, then they have very few slots. I mean, it happens in neuroendocrine tumors, so it’s not as easy to apply to the community. That also had to be worked out.

AMBIKA: The NCCN [National Comprehensive Cancer Network] just changed the guidelines yesterday, or the day before yesterday, so now the PSMAs [prostate-specific membrane antigens are] in the guidelines, even if at the time of diagnosis and at progression. So if you want to appeal it…you can use the NCCN now.

AGHALAR: The wording of the NCCN guidelines is still a little bit iffy. They say to consider PSMA agents as an alternative option, so we’ll see how the insurance companies react to that being in the guideline now. There’s a lot of inter- and intratumor heterogeneity, so understanding the disease biology continues to evolve and influence management and therapeutic development. Sequencing is an important component of the treatment planning.

Of course, androgen deprivation therapy, as we all know, remains a foundational therapy, even with the emergence of new therapies. The switching of the mechanism of action is associated with improved OS, so we’re very fortunate now in the last 10 years with the approval of multiple agents that we can turn to, that allows our patients to maintain quality of life and improve OS.

_REFERENCES

_{1. Ryan CJ, Smith MR, Fizazi K, et al; COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152-160. doi:10.1016/S1470-2045(14)71205-7}

_{2. Armstrong AJ, Lin P, Tombal B, et al. Five-year survival prediction and safety outcomes with enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate cancer from the PREVAIL trial. Eur Urol. 2020;78(3):347-357. doi:10.1016/j.eururo.2020.04.061}

_{3. Kluetz PG, Pierce W, Maher VE, et al. Radium Ra 223 dichloride injection: U.S. Food and Drug Administration drug approval summary. Clin Cancer Res. 2014;20(1):9-14. doi:10.1158/1078-0432.CCR-13-2665}

_{4. Fizazi K, Kramer G, Eymard JC, et al. Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus abiraterone or enzalutamide (CARD): an analysis of a randomised, multicentre, open-label, phase 4 study. Lancet Oncol. 2020;21(11):1513-1525. doi:10.1016/S1470-2045(20)30449-6}

_{5. 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}