Roundtable Discussion: Slovin Looks at the Sequencing of Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer

Susan Slovin, MD, PhD (Moderator)

Associate Vice Chair of Academic Affairs

Department of Medicine

Memorial Sloan Kettering Cancer Center

New York, NY

CASE SUMMARY

A 75-year-old man presented with intermittent right hip pain, but his physical exam was unremarkable. His clinical workup showed a prostate-specific antigen (PSA) level of 32.6 ng/mL, and his bone scan and abdominal/pelvic CT scan were negative. A transrectal ultrasonography biopsy showed he had a Gleason score 4 + 4 and Grade Group 4. He was diagnosed with stage T2N0M0 and an ECOG performance status of 1.

External beam radiation therapy plus androgen-deprivation therapy were initiated and planned for 18 months, but there was undetectable PSA level at 6-month follow-up and the testosterone at castration level was asymptomatic. However, 6 months later the patient developed new hip pain and urinary frequency, with a PSA level of 29.4 ng/dL and testosterone level of 10 ng/dL.

The patient was now considered metastatic and castration resistant, and he began treatment on enzalutamide (Xtandi) at 160 mg by mouth daily. Four months after beginning enzalutamide, the patient’s PSA level decreased to nadir of 3.9 ng/dL; after 8 months on enzalutamide, the patient had a PSA level of 60.7 mg/mL. He was started on docetaxel (Taxotere) at 75 mg/m² intravenously (IV) every 3 weeks and daily prednisone by mouth every 12 hours. After 6 cycles, the patient developed bilateral digital neuro-pathy and docetaxel was held. Then after 3 months, he had a rising PSA and new back pain.

SLOVIN: About a third of you want to repeat the next-generation sequencing [NGS] and cell-free DNA testing, but these are not mutually exclusive. You certainly could do both. Only 17% want to look toward the lutetium, which is very surprising because we are constantly deluged with people coming in and saying well, when is this miracle drug going to come to your institution? So, I’m surprised that only about 17% of people are interested in doing that. We got no votes for radium-223 [Xofigo], so it seems that radium may be falling out of popularity.

Anybody have any thoughts of what else they could do, or would like to do? There’s always [putting the patient on a] clinical trial, that would be reasonable.

PETRYLAK: [Radium] is clearly contraindicated for liver metastases at that point. It’s not going to help because radium doesn’t go [to the liver]. But one choice that’s not [presented] here, which I like using in this situation, is cabazitaxel [Jevtana] along with carboplatin. This is aside from [doing another biopsy] to see if [the cancer has] converted to a small cell type, which, given the elevated PSA [level], it probably hasn’t, although you can see biclonal disease [when] looking for MSI status or other DNA repair deficiencies if [the patient] develops a somatic mutation.

SLOVIN: I would agree, and sometimes, if [a patient is somewhat] frail, you could possibly get away with [giving the] carboplatin weekly, at 3 weeks on and 1 week off, which is reasonable to do. I have, on rare occasions, used paclitaxel even [in patients] who have neuropathic problems and I’ve managed [to give it] at low doses; sometimes giving [paclitaxel] at a low dose or weekly can [deliver] the drug [successfully]. Does anyone have any other comments?

ZHU: I think just based on the studies [¹⁷⁷Lu-PSMA-617 (Pluvicto)] also failed at least 1 second-generation [androgen receptor (AR) agonist] and 1 [chemotherapy regimen]. With cabazitaxel you can get a median progression-free survival [PFS] and have less benefit, so I want to say this patient also has indication of prostate-specific membrane antigen [PSMA] positive lesions scan on a PSMA scan.

SLOVIN: [Perhaps] you remember that at a recent American Society of Clinical Oncology [ASCO] Annual Meeting, Michael Hofman, MD, from Australia, was talking about his phase 3 trial of ¹⁷⁷Lu-PSMA-617 vs cabazitaxel [TheraP, NCT03392428]. He initially had shown, at the 20-month mark, that there had been an improvement in radiographic PFS and overall survival [OS].¹ [It was hoped that this benefit would continue, but] at this year’s ASCO meeting, the data showed that there was no [longer a] difference in OS.²

And the major question, of course, is how do you strategize? Do you give cabazitaxel first and then [¹⁷⁷Lu-PSMA-617]? Do you give [¹⁷⁷Lu-PSMA-617] first and then cabazitaxel? Just as a point of interest, [I want to note that] sometimes everybody gets excited about phase 3 [trial results] very early, because [the studies] often use radiographic PFS as a surrogate marker for OS. However, in this case, there was no significant difference [in OS].

DISCUSSION QUESTIONS

• How do you select next-line therapy for a patient with metastatic castration-resistant prostate cancer who has received docetaxel and an AR-targeted therapy?
• What factors to you consider when deciding treatment?
  • Patient fitness/performance status
  • Age
  • Prior therapy (response/tolerance)
  • Symptoms
  • Sites/extent of metastatic involvement
  • Nature/place of progression
  • Patient preference
  • Financial considerations
  • Logistics/convenience/access
  • Other

PETRYLAK: I look at how fast the disease is moving and whether the patient has visceral disease or not. [I also look at the] patient’s overall fitness. I think you [should consider whether their] fitness [is influenced more by] the metastases or by some other underlying condition. We’ve seen great improvements in bone pain [management and] great improvements in performance status in patients who respond but [were in] quite bad shape to begin with, so I think you’ve got to decide that carefully. And [increasingly], we’re seeing financial considerations [affecting] our patients.

The drug may or may not be approved by the insurance company. We’re seeing that particularly with [AR-targeted drugs]. You have to use your gut [to make this decision]. [Is the patient] progressing rapidly? Do they need chemotherapy? [Another thing to consider is that] we don’t know what the effect of [¹⁷⁷Lu-PSMA-617] is going to be on marrow suppression [and] whether the patient can get cabazitaxel or other myelosuppressive agents.

SLOVIN: At the ASCO meeting, I had to give a commentary, and a gentleman in the audience protested, “[The patients are] going to be dead in 10 years [anyway, so long-term toxicity does not matter].” [But] the reality is that [these patients] are not dead in 10 years. I have had patients with Gleason scores of 8 or 9, some of whom have been alive and kicking for 20 to 25 years. And [such patients] are not [rare]. A lot of patients are like that now, and we are affecting peoples’ lives, but we don’t know the long-term toxicity.

Does anybody else want to [share] what factors you would look at?

KAPPEL: I think [Dr Petrylak] brought up [several important] points. Patient preference, financial [considerations], logistics, [and the] nature and pace of progression [are] all standard [considerations] among all cancers. But [a particularly] important [consideration that he mentioned was] comorbidities. Prostate cancer may be one of those unique [cancers] where we’re dealing with older guys who have more comorbidities [and] who aren’t going to be able to tolerate some of these therapies. Their ability to take multiple lines of therapy [may be less than that of other patients with other cancers]. A lot of these patients are in their 80s, so they’re not eligible for multiple lines of therapy.

SLOVIN: You’re absolutely right.

MO: I [would take] the patient’s symptoms and their performance status [into consideration]. I totally agree with Dr Kappel. I [would consider] going to cabazitaxel, [and] I would think about decreasing the dose [to] 20 mg because I worry about pneumonitis.

BRAUNSTEIN: The duration of prior response and other comorbidities would be at the top of my list, and the symptoms are [also] important [to consider].

SLOVIN: Yes, I think we’re probably all in accord with these things, but a lot of [the treatment process] depends on patient compliance. There’s no question. I’m [dealing] with patients going to Florida and wanting to get their care there. It ends up [being] difficult to manage these patients.

DISCUSSION QUESTION

• A decision was made to start cabazitaxel. What starting dose would you most likely use?
  • 25 mg/m²
  • 20 mg/m²
  • Other

SLOVIN: [In a comparison of] cabazitaxel, either 20 mg/m² or 25 mg/m², vs docetaxel [FIRSTANA; NCT01308567], [researchers] found that the [2 cabazitaxel dosages] were comparable [From The Data³]. I think most physicians use 20 mg/m² because it has less toxicity. I personally do not use pegfilgrastim [Neulasta] if I’m using the 20 mg/m²-dose, and I’ve never had any problems with neutropenic fever. [Have you had] any problems when you’ve used [cabazitaxel]?

PETRYLAK: No, I haven’t. [Granted, I’m a little more cautious] and I do use pegfilgrastim, but no, I haven’t had trouble. The real issue with [cabazitaxel] is diarrhea, [but overall] it’s better tolerated than docetaxel [and causes] less neuropathy. In fact, in patients who need [to maintain] manual dexterity and who are worried about neuropathy, I’ve used this frontline. This is off-label, but I’ve done it that way with fairly good results. In fact, the data from the randomized trial of frontline docetaxel vs cabazitaxel showed no difference in survival, and the neuropathy was [better with cabazitaxel].³ And that’s [a facet of the data] that was never emphasized.

SLOVIN: I’m surprised that you are able to give it in the frontline. I’ve never been able to do that.

PETRYLAK: I’ve only tried twice, but I’ve gotten it. This was for 2 [patients] who needed it.

SLOVIN: That’s understandable. Is anybody else using it in the front line?

ZHU: I never use [it in the front line].

KAPPEL: I haven’t used it in the front line. but I want to emphasize that paclitaxel is even worse than docetaxel in terms of neuropathy. These patients have long-term neuropathy. It’s almost crazy to think that their neuropathy gets better because it just doesn’t. And it’s a horrible, horrible toxicity for a lot of people, quite debilitating. And paclitaxel is the worst.

SLOVIN: [According to] the National Comprehensive Cancer Network [NCCN] guidelines on the use of cabazitaxel, you could use 20 mg/m² or 25 mg/m².⁴ You could use it with a steroid,⁴ [though] I personally don’t. I don’t use growth factor, but I think you need to determine whether [your patient has] been very heavily pretreated and make a decision. [The NCCN guidelines also offer] cabazitaxel plus carbo[platin] [as an option].⁴ I’ve used that, and I do agree that [the combination] can be gentle relative to either drug.

DISCUSSION QUESTIONS

• Would you give cabazitaxel to a patient who did not tolerate docetaxel well?
• If this patient had completed 6 or more cycles of docetaxel, would your recommendation differ?
• Have you used carboplatin plus cabazitaxel? If yes, please share your experience. In what scenario(s) did you use it?

SLOVIN: Would [anyone here choose to use ¹⁷⁷Lu-PSMA-617] or something else? I don’t think it makes a difference how many cycles [of docetaxel the patient has had]. This [patient] only got 4 [cycles] and had problems. In a case like this, if a patient had very bad neuropathy and I had [¹⁷⁷Lu- PSMA-617] available and the patient was, of course, PSMA-avid, I probably would vote for [¹⁷⁷Lu-PSMA-617] before giving cabazitaxel.

I think, Dr Petrylak, you and I have both [used carboplatin plus cabazitaxel], and that combination is tolerable. Dose modifications, I think, depend on their [labs] and how the patient is feeling. I [had] a patient who was on docetaxel [and] had a very short-lived response [and] progressive adenopathy, minimal bone but all adenopathy. And I [then used] carboplatin plus cabazitaxel, and, [as assessed] by fluorodeoxyglucose PET scan, [there was] a 95% response rate in terms of adenopathy regression. I did biopsy [at that point], and there were no actionable mutations. There was no neuroendocrine component, just high-grade prostate cancer. Is there anything you want to [share regarding] your experience with the carboplatin plus cabazitaxel combination?

PETRYLAK: Yes. The recommended dose is 20 mg/m² and [the target] area under the curve is 4 mg/mL min [with carboplatin].^5,6 I’ve had good experience with liver metastases with this [combination in] one of our patients, who was on a randomized trial of docetaxel plus or minus [an experimental] drug. [This patient] had liver metastases, and then he progressed in [the] liver. He’d had a good response to docetaxel, initially. And [there is no] neuroendocrine [carcinoma]; he’s been biopsied.

DISCUSSION QUESTION

• What is your opinon of the data from the CARD trial (NCT02485691) of cabazitaxel vs an AR-targeted agent?

SLOVIN: [I think we can all agree that the data are] compelling and will influence [our] practice. Everybody seems to be in favor of using the drug.

KAPPEL: [This discussion is] making me relook at chemotherapy in general.

SLOVIN: [Does] anybody have any other thoughts? Dr Petrylak and I like to use cabazitaxel. In terms of how to manage any major toxicities, as I said, I’ve never had to use pegfilgrastim [with] the 20 mg/m²-dose [of cabazitaxel]. I know some people [give pegfilgrastim] routinely. I don’t even give it with prednisone because some of our patients have already been on prednisone from prior chemotherapy. I [might] keep them on 5 mg [after] docetaxel [treatment]; I don’t want to increase it to 10 mg, for example.

[Another question is], how does everybody decide what to tell [patients]? Are we saying is it better, in most cases, if you have metastatic castration-resistant disease after hormone-based therapy, to do another AR-signaling inhibitor, maybe a clinical trial, or go to a second-line chemotherapy? Do you prefer IV [therapy] to oral [therapy for reasons of tolerability]? Does anybody have any thoughts on how they would make recommendations?

PETRYLAK: You can get just as sick with an oral drug as you can with an IV drug, sometimes even sicker. So, it’s more [a matter of] the tolerability [in general]. The [adverse] effect I’ve encountered the most with cabazitaxel recently has been some diarrhea. It [doesn’t happen] commonly, not as much as [with] the 25-mg dose. The 20-mg dose is very well tolerated, and usually the standard treatments for diarrhea [loperamide hydrochloride] and, if necessary, octreotide acetate [are sufficient]. But again, I think it is an incredibly well-tolerated drug.

SLOVIN: My only issue [with] oral medications is the potential interaction with other oral agents.

KAPPEL: [Regarding] steroids, I agree with you. With prednisone, it [can sometimes be] difficult to get people’s [dose] down; [but] you know, there’s no evidence that you need to give prednisone with docetaxel.

That’s been a debate from the beginning. There is no scientific evidence that [adding prednisone] is better than docetaxel alone.

SLOVIN: Yes, you’re right. Does anybody else want to comment [about] a preference for IV or oral [therapy]?

KAPPEL: I [prefer] IV over oral [therapy] because [with an IV drug], you know [for certain that] the patient is getting [the drug]. You can evaluate the patient and see how they’re doing. It may not necessarily be the better [out-of-pocket cost] for health care in general but for the patient, it’s the better [out-of-pocket cost]. Patients have a false impression that if [a drug is] oral, it’s going to be better tolerated than an IV drug.

_REFERENCES

_{1. Hofman MS, Emmett L, Sandhu SK, et al. TheraP: a randomised phase II trial of 177Lu-PSMA-617 (LuPSMA) theranostic versus cabazitaxel in metastatic castration resistant prostate cancer (mCRPC) progressing after docetaxel: initial results (ANZUP protocol 1603). J Clin Oncol. 2020;38(suppl 15):5500. doi:10.1200/ JCO.2020.38.15_suppl.5500}

_{2. Hofman MS, Emmett L, Sandhu S, et al; The Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). TheraP: 177Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel—overall survival after median follow-up of 3 years (ANZUP 1603). J Clin Oncol. 2022;40(suppl 16):5000. doi:10.1200/ JCO.2022.40.16_suppl.5000}

_{3. Oudard S, Fizazi K, Sengeløv L, et al. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: a randomized phase III trial-FIRSTANA. J Clin Oncol. 2017;35(28):3189-3197. doi:10.1200/ JCO.2016.72.1068}

_{4. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 1.2023. Accessed October 11, 2022. https://bit.ly/3FYSgdd}

_{5. Jevtana. Prescribing information. Sanofi-Aventis US; 2021. Accessed October 12, 2022. https://bit.ly/3WJLcHe}

_{6. Carboplatin. Prescribing information. Hospira; 2021. Accessed October 13, 2022. https://bit.ly/3NIBeC6}