Discussing the Role of Cabazitaxel Post–Hormone Therapy for mCRPC

Atish D. Choudhury, MD, PhD

Chair of the Gelb Center for Translational Research

Senior Physician

Dana-Farber Cancer Institute

Assistant Professor of Medicine, Harvard Medical School

Boston, MA

CASE SUMMARY

A 75-year-old man presented with intermittent right hip pain. His physical exam was unremarkable except for a prostate nodule on rectal exam. Prostate-specific antigen (PSA) was 32.6 ng/mL, bone scan and abdominal/pelvic CT scan were negative. Transrectal ultrasonography biopsy showed Gleason 5 + 4 grade group 5. He was diagnosed with stage T2N0M0 prostate cancer, ECOG performance status was 1. He received external beam radiation therapy plus androgen deprivation therapy (ADT), planned for 24 months. He had an undetectable PSA level at 6-month follow-up and was asymptomatic.

Thirty-six months later, the patient developed new hip pain and urinary frequency. PSA was 29.4 ng/mL. Testosterone was 300 ng/dL. Bone scan showed evidence of 2 new lesions in the right hip (0.8 cm and 1.1 cm). Abdominal/pelvic CT showed a 2.1-cm left pelvic lymphadenopathy and blastic lesions corresponding to the uptake on bone scan. Germline and somatic testing were negative for pathogenic alterations.

The patient started treatment on ADT plus enzalutamide (Xtandi) 160 mg by mouth daily. PSA decreased to a nadir of 3.9 ng/mL 4 months after starting enzalutamide and bone pain resolved. 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. Bone scan showed progressive disease. He had new back pain and progressive fatigue, with ECOG performance score remaining at 1. He was now considered metastatic and castration resistant.

The patient was started on docetaxel 75 mg/m² intravenously every 3 weeks and daily oral prednisone 10 mg. He clinically responded with resolution of pain and improved energy, with a declining PSA​. With 4 cycles completed, the patient developed worsening bilateral digital neuropathy throughout therapy, so therapy was stopped during cycle 5.

After 3 months, he had rising PSA, new back pain, and shortness of breath on exertion. Imaging shows enlargement of known pelvic lymph nodes and 1 new liver lesion (<2 cm). Next-generation sequencing was performed and showed no actionable mutations.

DISCUSSION QUESTIONS

• Would you give cabazitaxel (Jevtana) to a patient who did not tolerate docetaxel well?​
• What if this patient had completed ≥6 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? ​

ATISH D. CHOUDHURY, MD, PhD: Have you given cabazitaxel to patients who do not tolerate docetaxel well?

ALESSIA DONADIO, MD: I have; there is probably a little less neuropathy. In those patients who didn't tolerate docetaxel, I've used a lower dose, and have sometimes gotten away with a response and tolerability.

CHOUDHURY: Does it matter that this patient had to stop docetaxel early? Would you consider docetaxel rechallenge in this particular patient if they had received all 6 cycles without having to stop?

DONADIO: If they had received all 6 cycles, I typically would rechallenge with docetaxel, especially if there has been some interval of time of stability in between that they might have had a more durable response.

CHOUDHURY: There is no randomized trial of docetaxel rechallenge versus cabazitaxel to know who the appropriate candidates are for [each one].

PETER GEORGES, MD: I have not personally [used carboplatin/cabazitaxel]. I did have a patient recently who had a BRCA2 mutation, and who was an elderly gentleman. He was treated with a couple years of olaparib [Lynparza] and had docetaxel already, [then] I decided to treat him with single-agent [chemotherapy], because of his age and comorbidities. Right now, he's getting his ¹⁷⁷Lutetium-PSMA-617 [Pluvicto]; he is PSMA [prostate-specific membrane antigen]-positive. I almost [gave him cabazitaxel], but then Pluvicto got approved, and he ended up going on PSMA-[targeted therapy].

CHOUDHURY: That's good for that patient. Dr D’Silva, have you used the combination [of carboplatin and cabazitaxel]?

KARL J. D’SILVA: Yes, I've used it on one patient [who] had extensive visceral involvement and he progressed on the androgen-receptor blocker abiraterone. I also gave him docetaxel, and at that point, everybody goes to [Dana-Farber Cancer Institute] to get the recommendation. He [was recommended for] carboplatin and cabazitaxel, so I…[had to ask whether insurance] would approve it. It was approved because there were some good data, especially with [visceral] involvement. The patient has been doing well. He is responding. I think carboplatin does add benefit to the cabazitaxel.

CHOUDHURY: What did you think of the tolerability? Were you nervous about the tolerability, and what are you now seeing with that particular patient?

D’SILVA: At the first cycle, he had developed neutropenia and had to be admitted in the hospital, but the second cycle, we got approval for growth factor support. He just finished his sixth cycle, and he continues to show response.

CHOUDHURY: This regimen is in the NCCN [National Comprehensive Cancer Network] guidelines.¹ What I found very interesting is that in [a study; NCT01505868], they gave carboplatin in combination with cabazitaxel at 25 mg/m² [every 3 weeks].² But if you looked in the NCCN guidelines, it says cabazitaxel at 20 mg/m², which is what we are routinely using…even though that's not what was tested in the trial.¹

BHUVANA RAMKUMAR, MD: I have not used this combination of carboplatin with cabazitaxel, because post-docetaxel [patients] with neuropathy…are already pretty beat up, with adverse events and low [blood cell] counts. What dose of carboplatin would you start with?

CHOUDHURY: AUC4 [area under the curve of 4] is the dose of carboplatin, and again, the published data was on cabazitaxel at 25 mg/m², but that's not what we use. We use cabazitaxel at 20 mg/m².

Dr Kilbridge, do you want to talk about your perspective of what tolerability of this regimen is compared with cabazitaxel monotherapy?

KERRY KILBRIDGE, MD: I found it remarkably tolerable. If I'm very worried about the patient being beat up at baseline, and I feel strongly that I want to get them on platinum therapy—that this looks like it's clearly an aggressive variant tumor—then I will dose reduce at the outset. I'll take [the carboplatin] down to an AUC of 3, and dose reduce the cabazitaxel down to 80% dose. Just for tolerability, particularly if there are comorbidities, but I favor using the combination as early as possible. I don't like to rechallenge. Especially in the CRPC space, we're talking about patients who will have limited bone marrow reserve over the trajectory of their disease, and so I try to be aggressive up front.

CHOUDHURY: I often do find that the cabazitaxel combination with carboplatin is a bit better tolerated than the docetaxel combination, because of the neuropathy issues and nausea and things along those lines, so I do tend to favor this regimen over the carboplatin/docetaxel regimen as well.

SHEILA DONNELLY, MD: What triggers you to use that combination of carboplatin/cabazitaxel over cabazitaxel by itself; a very symptomatic patient [or] very aggressive disease?

GLENN J. BUBLEY, MD: It used to [be based on] when they have multiple bad mutations, like P53 and P10 loss.

CHOUDHURY: You can use the molecular features: 2 of the 3 tumor suppressors, P53, P10, and Rb loss, is one factor for it; also if they have a very aggressive variant, [such as with] lots of visceral metastases with very low PSA production; or you've done a biopsy, and maybe it's not full-on small cell [carcinoma], but there are some neuroendocrine features that looked very de-differentiated, and things along those lines. I would think about doing platinum therapy upfront with cabazitaxel. There are other cases where I've used cabazitaxel monotherapy, gotten through 2 cycles, and seen that they haven't had a response; then I might add the carboplatin for the third of fourth cycle.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 1.2023. Accessed November 29, 2022. https://bit.ly/3XVslKf}

_{2. Corn PG, Heath EI, Zurita A, et al. Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1-2 trial [published correction appears in Lancet Oncol. 2020 Jan;21(1):e14]. Lancet Oncol. 2019;20(10):1432-1443. doi:10.1016/S1470-2045(19)30408-5}