Cabazitaxel Advances Later-Line Treatment in Metastatic CRPC Setting

A. Oliver Sartor, MD

During a Targeted Oncology Case-Based Roundtable event, A. Oliver Sartor, MD, C. E. & Bernadine Laborde professor of Cancer Research, medical director, Tulane Cancer Center, and assistant dean for Oncology at Tulane University School of Medical, discussed the results of cabazitaxel (Jevtana) as a later-line treatment for patients with metastatic castration-resistant prostate cancer (CRPC).

Targeted Oncology^TM: What are the initial options for treatment for this patient population?

SARTOR: The NCCN [National Comprehensive Cancer Network] guidelines give you plenty of options. You have category 1, but it is based on older data prior to the use of the abiraterone [Zytiga] and enzalutamide.¹ I cannot imagine using mitoxantrone in this circumstance, to be honest. The fine-particle abiraterone is just a variation on abiraterone, and other secondary hormones I wouldn’t utilize.

One of the tactics that we use for cost-effectiveness sometimes is using the abiraterone with food instead of fasting and using a little lower dose. Sometimes we encounter co-pay problems; the drug costs are high. Using the abiraterone with food is something that we do on occasion.

Please describe the rationale and design for the trial that looked at the use of cabazitaxel.

This is the [phase 4] CARD trial [NCT02485691] where patients had metastatic CRPC [castration-resistant prostate cancer]. Patients progressed after less than 12 months on a prior alternative novel hormone—in this case, it’s one of the newer androgen receptor [AR]–targeted agents, such as abiraterone and enzalutamide. They enrolled 255 patients, randomized 1:1 between cabazitaxel and either abiraterone or enzalutamide. The primary end points were radiographic progression- free survival [rPFS], with key secondary end points of overall survival [OS], progression-free survival [PFS], PSA, etc.²

[This was] not a young population, [aged] about 70 to 71 years, which I think is typical from our practice. The vast majority had an ECOG performance status 0 to 1 and visceral metastases [were] relatively well balanced in both groups. The type of progression at the time of study entry was often [when the patient was experiencing] pain, and that’s interesting because I think we’ve gotten accustomed to looking at a lot of these studies where it’s PSA-only progression, but a lot of these patients had pain progression.

Most patients also had Gleason score 8 to 10 and a substantial number, but certainly not the majority, had M1 disease at diagnosis. Patients received docetaxel [Taxotere] or abiraterone only in a minority for metastatic hormone-sensitive or castration-sensitive cancer. The prior alternative AR-targeted agent was abiraterone or enzalutamide, and this was relatively well balanced. They received it either before or after docetaxel in an equal fashion. The median duration of the alternative AR-targeted agent, the abiraterone and enzalutamide that proceeded the randomization, was about 7.6 to 8 months.

What were the efficacy outcomes of this study?

The primary end point of rPFS had a very strong hazard ratio of 0.54 [95% CI, 0.40-0.73; P < .0001]. Median rPFS was 8 months versus 3.7 months in [the cabazitaxel and hormone therapy arms, respectively].3 This was not a particularly good performance from the hormones therapy with a P value less than .001, so quite strong data [for cabazitaxel]. All the subgroups seemed to benefit from the cabazitaxel, and there was no subset identified where the hormonal agent was better.

The trial was not powered for OS, but it was positive anyway. The hazard ratio was 0.64 [95% CI, 0.46-0.89; P = .0078] and it had a relatively modest median of 13.6 months to 11 months [in the cabazitaxel and abiraterone or enzalutamide arms, respectively]. For PFS, which would include not just the rPFS but the symptomatic progression, there was benefit. The hazard ratio for PFS was 0.52 [95% CI, 0.40-0.68; P < .0001], so again, PSA responses were also statistically significant [P = .0002], objective tumor response was statistically significant [P = .004], and pain response was also statistically significant [P < .0001], with everything favoring the cabazitaxel arm. There was also a strong trend in time to SSE [symptomatic skeletal events] even with the median SSE not reached [P = .05]. there was a clear benefit here.

What were the adverse events (AEs) associated with these data?

AEs are going to happen, but serious AEs were balanced, 38.9% to 38.7% [in the cabazitaxel and abiraterone or enzalutamide arms, respectively].4 The grade 3 or higher AEs [were more in the cabazitaxel arm], 56.3% to 52.4%. AEs leading to discontinuation were 19.8% [in the cabazitaxel arm, which was] acceptable. AEs leading to death, however, were higher in the abiraterone or enzalutamide arm.

[The probability of deterioration at 3 months] performed well and adjusted mean changes from baseline on the pain scales, well-being scales, and a pain benefit with a P value of less than .001.5 Clearly, a better pain-related subscale on the quality-of-life scores.

How do these data affect your practice and treatment decisions?

I was one of the coinvestigators on [a trial] published way back in 2010 with cabazitaxel. I’ve had a fair amount of experience in terms of using it. It’s a dose-related phenomenon; I tend to use the 20 mg/m² to get going, but it’s an effective agent. I don’t think there’s any doubt about cabazitaxel being able to be active in the docetaxel-progressing patients. This setting was where docetaxel was discontinued because of toxicity and clearly cabazitaxel is available there. So these are good data.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 2.2020. Accessed May 3, 2021. https://bit.ly/3tgVTBo}

_{2. 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;381(26):2506-2518. doi:10.1056/NEJMoa1911206}

_{3. Fizazi K, et al. Pain response and health-related quality of life (HRQL) analysis in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving cabazitaxel (CBZ) versus abiraterone or enzalutamide in the CARD study. J Clin Oncol. 2020;38(suppl 6):16. doi:10.1200/JCO.2020.38.6_suppl.16}

_{4. de Wit R, Kramer G, Eymard JC, et al. CARD: randomized, open-label study of cabazitaxel (CBZ) vs abiraterone (ABI) or enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2019;30(suppl 5):v851- v934. doi:10.1093/annonc/mdz394}

_{5. 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}