CARD Trial Establishes Cabazitaxel as a Third-Line Standard in mCRPC

Celestia S. Higano, MD, FACP

Cabazitaxel (Jevtana) has become a third-line standard of care in men with metastatic castration-resistant prostate cancer (mCRPC), according to findings from the phase III CARD trial, said Celestia S. Higano, MD, FACP.

The CARD trial enrolled patients with mCRPC who had previously received docetaxel and progressed within 1 year of receiving either abiraterone acetate (Zytiga) or enzalutamide (Xtandi). In the study, patients who received cabazitaxel as third-line therapy had a median imaging-based progression-free survival (PFS) of 8.0 months versus 3.7 months in those who received the antiandrogen that they had not progressed on (HR, 0.54; 95% CI, 0.40-0.73; P <.001).

Moreover, the median overall survival (OS), which served as a secondary endpoint of the trial, was 13.6 months with cabazitaxel versus 11.0 months with either antiandrogen (HR, 0.64; 95% CI, 0.46-0.89; P =.008). The use of cabazitaxel also showed a clinically meaningful improvement in pain response and time to skeletal-related events (SREs) versus abiraterone or enzalutamide.

“The patients in the study are patients we often see in the clinic,” said Higano. “These data should encourage more clinicians to give cabazitaxel to this population of patients rather than the alternative hormonal agent.”

In addition to confirming suspicions that sequential therapy with abiraterone and enzalutamide is not beneficial in men with mCRPC, the data showed a comparable rate of adverse events (AEs) in patients who received cabazitaxel or an antiandrogen.

In an interview with OncLive, Higano, a professor of medicine and urology at the University of Washington and Fred Hutchinson Cancer Research Center, and a physician in the Seattle Cancer Care Alliance, provided perspective on these data and their implications on clinical practice.

OncLive: Could you provide background on the CARD trial?

Higano: At the 2019 ESMO Congress, Ronald de Wit, MD, PhD, of Erasmus MC Cancer Institute, presented the data from CARD, which is a landmark study that established the use of cabazitaxel as third-line therapy in metastatic CRPC. In the trial, patients had to have been treated with docetaxel and [progressed within 1 year of receiving] either abiraterone or enzalutamide. Patients were randomized 1:1 to receive cabazitaxel or the other novel antiandrogen agent they did not receive—either abiraterone or enzalutamide—depending on what they had received before. The primary endpoint of the trial was radiographic progression-free survival (rPFS). The secondary endpoints were OS, PFS, prostate-specific antigen response, tumor response, and importantly, pain response.

Could you elaborate on the trial findings?

We use rPFS [as a primary endpoint] because OS has been confounded by so many therapies that are often given after a trial. In this trial, rPFS was significantly better with cabazitaxel. The median rPFS with cabazitaxel was 8.0 months versus 3.7 months with abiraterone or enzalutamide, which translated into an overall decreased risk of progression of 46% compared with abiraterone or enzalutamide. The hazard ratio was 0.54, and the P value was very significant. In terms of secondary endpoints, OS was also improved with cabazitaxel. The median OS was 13.6 months with cabazitaxel versus 11.0 months with the hormonal agents. We also saw a clinical benefit in terms of pain response and time to SREs, both of which were significantly better in the cabazitaxel arm versus the hormonal arm.

Were the AEs comparable between the 2 arms as well?

Yes, and that may be [contrary] to what people might think. Initially, there was a lot of concern [with regard to increased AEs with cabazitaxel]. However, once we started to use [the agent] in practice, we learned how to deal with some of the AEs [associated with its use] like neutropenia, or even more importantly, prevent them. It's interesting that this trial showed that there was no difference in AEs between a chemotherapy agent and hormonal therapy. The tolerance of cabazitaxel in practice is very consistent [with the trial data]. It’s gratifying to see the results of this trial.

Prior to these data, what did third-line treatment consist of?

In our academic center, we tried to put patients on clinical trials. Many trials are now requiring patients to have prior docetaxel and either abiraterone or enzalutamide. I haven't been a fan of using abiraterone or enzalutamide sequentially because the data are not very impressive. It wasn’t uncommon that I would give cabazitaxel before the study was available.

How have these data helped address some unanswered questions in this space?

Many drugs have shown clinical benefit in terms of OS or rPFS, but we haven't really known how to sequence them. This study, along with several others, really put us on notice regarding the use of abiraterone after enzalutamide or enzalutamide after abiraterone, particularly when the duration of response (DOR) is less than 12 months. In the trial, the DOR to either hormonal agent had to be 12 months or less. Based on these data, we really need to think more about using chemotherapy, specifically cabazitaxel. We saw very impressive responses with cabazitaxel versus the alternative novel antiandrogen agent.

Should cabazitaxel be considered the third-line standard in mCRPC?

We have to call it a third-line standard, not the third-line standard because there are other populations of patients that were not studied in this trial. For example, patients who had a very long DOR to either abiraterone or enzalutamide were not eligible for the trial. We still don't know about patients who have biomarkers, such as BRCA1/2 mutations, and can be treated with a PARP inhibitor, or patients who might be eligible to be treated with an [immunotherapy] agent, such as pembrolizumab (Keytruda).

The other population that the CARD trial didn't address is those patients who are not suitable to receive chemotherapy. The kinds of patients I see who are not fit for chemotherapy are usually ready for hospice—not another line or therapy. However, it would be nice if there was something for patients who might have problems with chemotherapy, whether it be with the alternative hormonal therapy [or another agent]. That will be the subject of future trials.

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.