Cabazitaxel Shows Improved Efficacy Compared With Androgen Receptor in Metastatic CRPC

A. Oliver Sartor, MD

During a Targeted Oncology Case-Based Roundtable event, A. Oliver Sartor, MD, the C.E. and Bernadine Laborde professor of Cancer Research, and medical director, Tulane Cancer Center Assistant Dean for Oncology Tulane Medical School, reviewed the case of a 75-year-old man with metastatic castration-resistant prostate cancer.

Targeted Oncology^TM: Do you consider the androgen receptor (AR)-V7 mutation status when determining treatment for a patient such as this?

SARTOR: I have not, and I’m probably not alone in that. AR-V7 is just 1 mechanism of resistance; it is important, but at the same time, you can probably give a short course of the second hormone, if that’s what you want to do, and f ind out for yourself.... The AR-V7 is just 1 of many [other mechanisms of resistance]. You can have AR amplification, you can have expression of non-AR genes, and the list goes on and on. AR-V7 works, but it’s only a piece of the puzzle and not a big piece.

There’s a phase 3 trial called PROSELICA [NCT01308580] that compared 20 mg/m² and 25 mg/m² [of cabazitaxel (Jevtana) with AR-V7], and it turned out [the results] were the same.1 The FDA has now approved either 20 mg/m² or 25 mg/m². I tend to start with 20 mg/m² and then if they do great, I can dose escalate, as opposed to starting with 25 mg/m2 and then deescalating if they run into trouble. That’s my style, I’m not sure if it’s right or wrong, it’s just that I generally start with 20 mg/m².

What was the design of the phase 4 CARD trial (NCT02485691)?

[Patients had to] have metastatic CRPC [castrationresistant prostate cancer] and had to progress while on abiraterone [Zytiga] or enzalutamide [Xtandi] and had to progress within 12 months.² In other words, if the patient had been a great responder to abiraterone or enzalutamide in the first place, then [they] wouldn’t even have been eligible for this trial.

On the novel hormones, you typically progress right around 12 months, so only about maybe half the patients [qualify] if you look at some of the data. However, this is not all comers, [and there are] patients who are progressing within 12 months on abiraterone or enzalutamide and then go on to docetaxel, or they’ve had docetaxel first and then go on to abiraterone/enzalutamide.

Patients are well balanced between the 2 arms [with] a significant percentage of characteristics [such as] visceral metastases....[There were] patients with highgrade malignancy at the time they were diagnosed, [and] a substantial proportion of patients were also metastatic at diagnosis. Patients [were on] abiraterone or enzalutamide, and they had typically received a little more abiraterone than enzalutamide in 1 arm versus the other. [Ultimately though,] it’s all the same, there are no big differences. Median duration of prior AR-targeted therapy was 7.6 months and 8.0 months, respectively. So that gets to the point of what I’m saying that this is not all comers. This is a subset of people who are progressing kind of rapidly on your AR-targeted agent [ARTA].

What were the outcomes of the trial? The primary end point was radiologic progression-free survival [rPFS], [at 8 months for patients on cabazitaxel compared with 3.7 months on abiraterone/enzalutamide, with a] hazard ratio of 0.54 [95% CI, 0.40-0.73; P < .0001], which is good. Pretty much every group was doing better with cabazitaxel, and it’s nice to see consistency across the board.

rPFS is one thing, but overall survival [OS] is another, and [looking at] the median OS is not that impressive, 13.6 months versus 11 months.3 But, the curves get more impressive over time, and the hazard ratio is 0.64 [95% CI, 0.46-0.89, P = .0078] for OS. To me, this was the meat of the study. I think if it had just been rPFS, it wouldn’t have [received] much publicity; but, with the OS benefit, that gets you in New England Journal of Medicine, and I think it gets you put in the National Comprehensive Cancer Network guidelines.

PFS, as opposed to rPFS, [also showed improvement in patients on cabazitaxel compared with abiraterone plus enzalutamide. Median PFS was 4.4 months in the cabazitaxel arm and 2.7 months in the abiraterone/ enzalutamide (HR 0.52; 95% CI, 0.40-0.68, P < .0001)].

Were there serious adverse events (AEs) seen in the trial?

PSA response was better with cabazitaxel than abiraterone/enzalutamide, 35.7% versus 13.5%, respectively.³ Objective tumor response was 36.5% among cabazitaxel patients compared with11%, and pain response was 45% versus 19%, respectively.

AEs leading to treatment discontinuation [were experienced in approximately] 20% for cabazitaxel. I may have started at 20 mg/m2 and had a little less than 20%, but this is what happened [on this trial].4 Grade 3 AEs [were experienced in approximately] 56% of patients on cabazitaxel and 52% in the other arm. AEs that led to death were more likely in the hormonal treatment arm, 11.3% compared with 5.6%. Serious AEs were pretty much the same. The pain subscale was positive in favor of cabazitaxel, and the prostate cancer–specific well-being had a trend [from baseline] but ultimately was not different. Overall, I think it was reasonably well tolerated.

How did other studies looking at cabazitaxel in this patient population present? The TROPIC trial [NCT00417079] with cabazitaxel showed the same trend. I was the coprincipal investigator on that trial and senior author on the manuscript, and cabazitaxel had the same pattern. It seemed [as though] the PFS benefit was modest, but the survival benefit was more than you would have expected.⁵ I’m not sure that I understand it, but we’ve seen it twice with this same agent. Generally, you have it in most hormone treatments; for instance, you have a big rPFS benefit, but the OS benefit is smaller. Here, it’s the opposite. You have a modest rPFS, but a big OS. I don’t know why.

What are your thoughts on cabazitaxel for this patient population?

I’ve been using it for a long time, as part of the original... phase 3 trial. The first thing you notice with any chemotherapy is that some individuals do much better than others. There were definitely patients who were resistant to docetaxel who could respond to this agent, and when it first came out, I was a little skeptical. Is this really a different taxane? Is it just somebody working around a patent and just trying to extend the patent life? I think it is a different taxane, and it has a different toxicity profile, and it really does work for those patients who are docetaxel resistant, not just those who may have been intolerant of docetaxel initially.

_References:

_{1. 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 Oct 1;35(28):3198-3206. doi:10.1200/ JCO.2016.72.1076}

_{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, Kramer G, Eymard JC, 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 Feb 19;38(6):16-16. doi:10.1200/ JCO.2020.38.6_suppl.16}

_{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. Oudard S. TROPIC: phase III trial of cabazitaxel for the treatment of metastatic castration-resistant prostate cancer. Future Oncol. 2011;7(4):497-506. doi:10.2217/fon.11.23}