Chemotherapy Utilized in Pretreated Metastatic Castration-Resistant Prostate Cancer
During a live virtual 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 OncologyTM: What do the National Comprehensive Cancer Network (NCCN) guidelines advise about the use of cabazitaxel (Jevtana) for metastatic castration-resistant prostate cancer (mCRPC)?
ANTONARAKIS: There are some guidances in the NCCN guidelines. A 20 mg/m2 or 25 mg/m2 starting dose can be used; both are FDA approved.1 The 25 mg/m2 dose has slightly higher objective response rate [ORR], but that did not translate into a longer progression-free survival [PFS] or overall survival [OS].
Then, in certain cases where you have a clinically-defined neuroendocrine prostate cancer or aggressive variant 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 with just cabazitaxel.2 So cabazitaxel/carboplatin is [recommended] for these patients that have clinical features suggestive of neuroendocrine prostate cancer like visceral metastasis, low prostate-specific antigen [PSA], bulky disease, high lactate dehydrogenase, high carcinoembryonic antigen, synaptophysin, or chromogranin. The 20 mg/m2 dose in terms of the myelosuppression, in my opinion, is much better tolerated. I still use growth factor support with the 20 mg/m2 dose as well. That is my personal preference, but I think the [risk of] grade 3 and grade 4 neutropenia and thrombocytopenia [is managed] better with the 20 mg/m2 dose.
Please discuss the study design and goals of the phase 4 CARD trial (NCT02485691) of cabazitaxel.
This is a pivotal study, which is called a phase 4 trial because it is a post-marketing trial. The CARD trial was done primarily in Europe, and this was for patients who had all received and progressed after 1 androgen receptor [AR]-targeted therapy and docetaxel. It was a third-line mCRPC, and this study was done in the days where we were not really using either of those agents in the metastatic hormone-sensitive setting. So the vast majority of these patients got both the taxane and the AR-targeting therapy for mCRPC in one sequence or the other.3
A very important eligibility [requirement] for this trial that many people overlook is that in order to be eligible, the patients must have previously failed their AR-targeted therapy within less than 12 months, and the reason that this is important is with a first-line AR-targeted therapy for mCRPC, only about one-third of patients progress within 12 months—the median is closer to 18 months. So in a way, this trial was pre-selecting patients who had a clinical definition of more AR-indifferent disease.
The 2 arms were treatment with the alternative AR therapy or with cabazitaxel at the 25 mg/m2 dose every 3 weeks. The primary end point was called imaging-based PFS, but it was basically a radiographic PFS.
There were about 130 patients in the 2 arms. There were roughly equal number of patients over the age of 75 although slightly more older patients received cabazitaxel. [In the cabazitaxel arm, 66.7% of] patients had pain at the time of enrollment [versus 71.4% in the control arm]. There were more patients with M1 disease at diagnosis but de novo metastatic disease in the control arm of abiraterone [Zytiga] or enzalutamide [Xtandi].
In terms of the split between abiraterone and enzalutamide and the docetaxel, only [10.9% in the cabazitaxel arm and 14.3% in the control arm] had received 1 of those 2 agents in the metastatic hormone-sensitive case. Most of those patients received both agents for mCRPC. The median duration of the prior AR therapy was about 8.0 months in both groups. Remember that to be eligible, these patients had to have an ablation within 12 months. So those 2 estimates do not reflect the real-world median responsiveness to AR-targeted agents because the trial selected for those patients.
What were the results of the CARD trial?
The primary end point was positive favoring cabazitaxel with a pretty robust, almost 50%, relative improvement in progression with a hazard ratio [HR] of 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 to progression [for the cabazitaxel arm].3
In every single preplanned subgroup, the [HR for imaging-based progression or death] favored the cabazitaxel arm. Some of the upper limits of the confidence intervals did cross 1.0, but in my opinion, there was a very consistent trend favoring [cabazitaxel in] all or most subgroups. Interestingly, if you look at patients with visceral metastases, there was a very clear benefit in those without visceral metastasis [HR, 0.50; 95% CI, 0.36-0.69]. For those with visceral metastases, the cabazitaxel still showed a benefit, but the confidence interval crossed 1.0 and [the upper limit went] all the way up to 1.52 [HR, 0.79; 95% CI, 0.41-1.52]. But my interpretation of this is that there was a consistent benefit. The benefit did not seem to be restricted to just 1 or 2 different scenarios.
Composite PFS included both radiographic or symptomatic progression [or death]. So if a patient had a progressive bone pain even in the absence of radiographic progression, that would count. This did not include [an increase in] PSA in the definition of progression, and there was a big difference with a HR of [0.52; 95% CI, 0.40-0.68; P < .0001].
But the part that surprised everybody, including myself, and the aspect that made this trial so practice-changing in my opinion, was that the OS was also numerically and statistically different and different in a clinically meaningful way with a decreased rate of death of about 36%. The HR was 0.64 [95% CI, 0.46-0.89; P = .008].
Every secondary end point also favored the cabazitaxel group: PSA response, objective tumor response, and pain response as well as an improvement in the time-to-first skeletal symptomatic event.
What was the safety and tolerability observed in this trial?
The adverse events [AEs] were numerically greater in the cabazitaxel arm with about 20% of patients having to discontinue cabazitaxel because of AEs, whereas only 9% of patients who received abiraterone or enzalutamide had to discontinue because of AEs.
But despite the slight increase in AEs, the quality of life on the FACT-P [Functional Assessment of Cancer Therapy – Prostate] scale, cabazitaxel did better than abiraterone and enzalutamide whether you are talking about physical wellbeing, social wellbeing, emotional wellbeing, or functional wellbeing. [Looking at the] trends across time, on the prostate-specific wellbeing scale, it did not reach significance but the patients who received cabazitaxel are consistently above those who received abiraterone or enzalutamide, especially for the first 6 to 9 months, and then their pain-related [wellbeing] was superior and also statistically significant, meaning that cabazitaxel was more effective by 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 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. 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