Physicians Discuss the Addition of Cabazitaxel to Treatment in mCRPC

CASE SUMMARY

A 75-year-old man presented with intermittent left hip pain and his physical exam was unremarkable expect for a prostate nodule on a rectal exam. The patient had an ECOG performance score of 1 and a prostate-specific antigen (PSA) of 16.2 ng/mL with a transrectal ultrasound scan (TRUS) and biopsy Gleason 5 + 4 grade group 5. The patient was negative on bone scan and an abdominal/pelvic CT scan, but an x-ray of the pelvis indicated osteoarthritis. The patient was given a diagnosis of stage cT2N0M0 disease and the germline and somatic testing were negative for pathogenic alterations. The patient first initiated external beam radiation therapy (EBRT) plus androgen-deprivation therapy (ADT), but he eventually developed metastatic castration-resistant progression and started 75 mg/m2 docetaxel intravenously once every 3 weeks plus 10 mg a day of prednisone.

JOSHUA LANG, MD, MS: How do you select next-line treatment for a patient with metastatic castration-resistant prostate cancer [mCRPC] who has received docetaxel and an androgen receptor [AR]-targeted therapy? And what factors do you consider when deciding on that treatment, whether it’s patient fitness, performance status, age, prior therapy, or whether that was response or tolerance of that treatment? [Do you consider] symptoms from both the disease as well as the therapies that our patients have received? Also, to what extent do sites or extent of metastatic disease influence that decision, as well as the pace of progression?

Joshua Lang, MD, MS​

Associate Professor

Department of Medicine

School of Medicine and Public Health

University of Wisconsin​

Madison, WI

BETY CIOBANU, MD: Depending on the practice you have, the option after a patient progresses on AR and docetaxel [treatment] are not many, but cabazitaxel [Jevtana] is 1 of them. [In my opinion], the most important feature that will help you choose the next line of treatment is the residual toxicity from their previous treatment, and the patient’s [current] preference. I think those are the most important, or at least the first factors, that will factor into deciding the next step.

LANG: I completely agree, especially for this gentleman who had significant peripheral neuropathy from the docetaxel. Fortunately, it’s not an absolute, meaning that there are some patients, especially in dire situations or with very symptomatic disease, where a rechallenge with cabazitaxel may not necessarily exacerbate those symptoms of peripheral neuropathy; especially in that setting where we do have some other treatment options that we could consider.¹ I think it’s a great point, in terms of, is this a patient who would be eligible for lutetium Lu 177 vipivotide tetraxetan [Pluvicto] as well.

ANASTAS PROVATAS, MD: I usually try to [get them on cabazitaxel], after they tried lutetium Lu 177 vipivotide tetraxetan…. If they are not candidates for cabazitaxel, but have had docetaxel in the past and problems with cytopenias, whether they can continue cabazitaxel is always difficult due to neuropathy and other adverse events [AEs]. It is difficult to complete a 6-cycle course of docetaxel [or cabazitaxel], you usually can’t go beyond 6 cycles based on my experience.

LANG: Going beyond 6 cycles of either docetaxel or cabazitaxel is very difficult. I get the occasional patient who still works full-time during chemotherapy, enough that it gives me hope to give it a try. But every patient is different, and tailoring the therapies and the recommendations is critical.

JOSE PAREDES, MD: Do you know about the tumor mutation burden in this patient, and whether he would be a candidate for pembrolizumab [Keytruda]?

LANG: Great question, and the right question, too. Those are all the things we want to interrogate in a biopsy [and the subsequent] next-generation sequencing that’s performed. In this case, microsatellite instability [MSI] was not elevated and the tumor mutation burden was low in this patient. I think that’s another question that when I have second opinions…is to make sure that we are getting a recent biopsy. I think especially with a liver lesion, those are easier to access, and especially in soft tissue, you get good-quality DNA for sequencing. Bone biopsies are things that can be performed too. At the University of Wisconsin, we have [a high] success rate with bone biopsies for genetic testing, but it does require some extra effort on both the part of our interventional radiologists doing the biopsies, and our pathologists who freeze the sample, rather than doing fixation or decalcification.

DISCUSSION QUESTION

• Have you used carboplatin plus cabazitaxel? In what scenario(s) did you use it?

PAREDES: In this setting, I would try to use the combination of carboplatin and cabazitaxel. I think that there are indications that it works better.² And if you go back to the original studies that said docetaxel as the premier chemotherapy for prostate cancer, they are not that great [and much older now].

LANG: When we look at the TAX 327 trial that led to the FDA approval of docetaxel in 2004, we had few to no options and the comparators were mitoxantrone and weekly docetaxel.³ So that’s where the [once every 3 weeks] regimen was shown to be superior, but the median survival was only 2 months, in terms of improvement for those gentlemen. So that is also why I think carboplatin, especially for patients with visceral involvement and liver metastases, has higher response rates.

We [need to] think of duration of response as well. But sometimes we see high-risk genomic mutations such as p53 or PTEN. Those are genomic mutations where if we see any, or any combination of those also in the setting of liver metastases, it is a disease that could be life-threatening within 6 months. These are just some other reasons to consider a more aggressive chemotherapy regimen [for these patients]. Are there other experiences from the group?

ROBERTO MONTOYA, MD: I used cabazitaxel and I have used it after docetaxel. Also, I always try to use it indefinitely in my patients as I have seen it is much better tolerated than docetaxel. I have been able to give it for more than 6 cycles to quite a few patients. It is not that we have a lot of chemotherapy options to use. I have not used carboplatin, paclitaxel, and cabazitaxel yet, but even if a patient doesn’t tolerate docetaxel, I still can use cabazitaxel. I have used it before, and patients have tolerated it much better.

LANG: That is very helpful, and I agree that we can see those responses. Unfortunately, we are already seeing these patients every 3 weeks, so if we do need to make a change away from cabazitaxel, most of those AEs resolve quickly except for the challenges that our patients face with peripheral neuropathy.

NISHANT PODDAR, MD: What is the incidence of typhlitis that you have seen with cabazitaxel in the elderly population? I have seen it twice and 1 [case] was fatal.

LANG: When we look at the compendium, the incidence of typhlitis was less than 1%. However, it is important to recognize. Do you happen to know what dose was used? Was it at 20 or 25 mg?

PODDAR: I don’t remember. It was long while back when it was approved.

LANG: If it was back when it was first approved, it was likely at the 25 mg/m² dose, which is the dose that I was administering back then and that was before we had the randomized trial of 20 mg/m2 vs 25 mg/m². So, especially at that 25 mg/m² dosing, the incidence…typhlitis was a less common toxicity, but certainly can still occur.² But that 25 mg/m² dose, the incidence of infectious neutropenia was approaching 10%, which is so terrible. And the toxicity death rates, people dying from infectious complications, was around 5%. [In that case, it was] very high risk, especially at that 25 mg/m² dose.

^References:

^{1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer; version 1.2023. Accessed June 19, 2023. https://bit.ly/3CV8ce1}

^{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. Lancet Oncol. 2019;20(10):1432-1443. doi:10.1016/S1470-2045(19)30408-5}

^{3. Tannock IF, de Wit R, Berry WR, et al; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-12. doi:10.1056/NEJMoa040720}