During a virtual live event, Emmanuel S. Antonarakis, MD, discussed the results of the CARD trial of cabazitaxel for patients with metastatic castration-resistant prostate cancer. This is part 1 of 2 articles based on this event.
Targeted oncologyMT: What do the National Comprehensive Cancer Network (NCCN) guidelines advise on the use of cabazitaxel (Jevtana) for metastatic castration-resistant prostate cancer (mCRPC)?
ANTONARAKIS: There are some tips in the NCCN guidelines. At 20 mg/m2 or 25mg/m2 the initial dose can be used; both are FDA approved.1 The 25 mg/m2 dose has a slightly higher objective response rate [ORR]but this did not translate to longer progression-free survival [PFS] or overall survival [OS].
Then in some cases where you have clinically definite neuroendocrine prostate cancer or an aggressive variant of prostate cancer, there is a Lancet Oncology publication showing that cabazitaxel 20 mg/m2 plus carboplatin 4 mg/mL/min was superior in terms of PFS compared to cabazitaxel alone.2 Cabazitaxel/carboplatin is therefore [recommended] for those patients who present with clinical features suggestive of neuroendocrine prostate cancer such as visceral metastases, low prostate-specific antigen [PSA], bulky disease, elevated lactate dehydrogenase, elevated carcinoembryonic antigen, synaptophysin, or chromogranin. The 20 mg/m2 dose in terms of myelosuppression, in my opinion, is much better tolerated. I always use growth factor support with the 20 mg/m2 dose too. It’s my personal preference, but I think the [risk of] grade 3 and grade 4 neutropenia and thrombocytopenia [is managed] better with 20 mg/m2 dose.
Please discuss the study design and objectives of the CARD (NCT02485691) Phase 4 trial of cabazitaxel.
This is a pivotal study, called a phase 4 trial because it is a post-marketing trial. The CARD trial was carried out mainly in Europe, and it was for patients who had all received and progressed after 1 androgen receptor [AR]-targeted therapy and docetaxel. This was a third-line mCRPC, and this study was done when we weren’t really using either of these agents in the hormone-sensitive metastatic setting. Thus, the vast majority of these patients received both taxane and AR-targeting therapy for mCRPC in one sequence or the other.3
A very important eligibility [requirement] for this trial that a lot of people forget is that to be eligible patients must have already failed AR targeted therapy within 12 months, and the reason this matters is with first line AR targeted therapy for mCRPC, only about a third of patients progress within 12 months – the median is closer to 18 months. So, in a way, this trial pre-selected patients who had a clinical definition of disease that was more indifferent to RA.
The 2 arms were treated with alternative AR therapy or with cabazitaxel at a dose of 25 mg/m2 dose every 3 weeks. The primary endpoint was called imaging-based PFS, but it was basically radiographic PFS.
There were approximately 130 patients in the 2 arms. There were about the same number of patients over the age of 75, although slightly older patients received cabazitaxel. [In the cabazitaxel arm, 66.7% of] patients had pain at enrollment [versus 71.4% in the control arm]. There were more patients with M1 disease at diagnosis but de novo metastatic disease in the abiraterone control group [Zytiga] or enzalutamide [Xtandi].
In terms of the split between abiraterone and enzalutamide and docetaxel, only [10.9% in the cabazitaxel arm and 14.3% in the control arm] had received 1 of these 2 agents in the hormone-sensitive metastatic case. Most of these patients received both agents for mCRPC. The median duration of prior antiretroviral therapy was approximately 8.0 months in both groups. Remember that to be eligible, these patients had to undergo an ablation within 12 months. These 2 estimates therefore do not reflect the true median reactivity to AR-targeting agents, as the trial was selected for these patients.
What were the results of the CARD trial?
The primary endpoint was positive in favor of cabazitaxel with a fairly robust relative improvement of almost 50% in progression with a hazard ratio [HR] by 0.54 [95% CI, 0.40-0.73; P < .001]and the median PFS results were quite different: 3.7 months to progression [for the comparator arm] for versus 8.0 months until progression [for the cabazitaxel arm].3
In each pre-planned subgroup, the [HR for imaging-based progression or death] favored the cabazitaxel arm. Some of the upper bounds of the confidence intervals crossed 1.0, but in my opinion there was a very consistent trend favoring [cabazitaxel in] all or most of the subgroups. Interestingly, if you look at patients with visceral metastases, there was a very clear benefit in those without visceral metastases [HR, 0.50; 95% CI, 0.36-0.69]. For those with visceral metastases, cabazitaxel still showed benefit, but the confidence interval crossed 1.0 and [the upper limit went] up to 1.52 [HR, 0.79; 95% CI, 0.41-1.52]. But my interpretation of that is that there was a consistent advantage. The benefit doesn’t seem to be limited to just 1 or 2 different scenarios.
Composite PFS included both radiographic or symptomatic progression [or death]. So if a patient had progressive bone pain even in the absence of radiographic progression, that would count. This did not include [an increase in] PSA in defining progression, and there was a big difference with an FC of [0.52; 95% CI, 0.40-0.68; P < .0001].
But the part that surprised everyone, myself included, and the aspect that made this trial so revolutionary in my opinion, is that the operating system was also numerically and statistically different and different from a clinically significant way with a decrease in the mortality rate of approximately 36%. HR was 0.64 [95% CI, 0.46-0.89; P = .008].
Each secondary endpoint also favored the cabazitaxel group: PSA response, objective tumor response and pain response as well as an improvement in time to first symptomatic bone event.
What was the safety and tolerability observed in this trial?
Adverse events [AEs] were numerically greater in the cabazitaxel arm with approximately 20% of patients having to discontinue cabazitaxel due to AE, whereas only 9% of patients receiving abiraterone or enzalutamide had to discontinue due to IS.
But despite the slight increase in AEs, the quality of life on the FACT-P [Functional Assessment of Cancer Therapy – Prostate] scale, cabazitaxel outperformed abiraterone and enzalutamide, whether you were talking about physical well-being, social well-being, emotional well-being, or functional well-being. [Looking at the] trends over time, on the prostate-specific well-being scale, this did not reach significance, but patients who received cabazitaxel are consistently superior to those who received abiraterone or enzalutamide, especially for the first 6-9 months, then their pain-related pain [wellbeing] was superior and also statistically significant, meaning cabazitaxel was more effective in controlling pain and preventing pain progression.
1.NCCN. Clinical practice guidelines in oncology. Prostate cancer, version 4.2022. Accessed June 13, 2022. https://bit.ly/3xNDAcB
2. Corn PG, Heath EI, Zurita A, et al. Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancer: a randomized, open-label, phase 1-2 trial. Lancet Oncol. 2019;20(10):1432-1443. doi:10.1016/S1470-2045(19)30408-5
3. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206