Third-line in mCRPC: CARD trial

Cabazitaxel third-line treatment offered statistically significant radiologic progression-free survival benefit over alternative anti-androgen therapy in pretreated castration-resistant prostate cancer (mCRPC) patients [1]. The data were simultaneously published in The New England Journal of Medicine [2].

Several agents are available for mCRPC patients with overall survival benefit, including abiraterone, cabazitaxel, docetaxel, enzalutamide, radium-223, and sipuleucel-T. However, due to a lack of head-to-head trials, the optimal sequence as to when to give these medications is unclear. Of note, a clear-cut third-line agent has not been approved, and the best treatment option after docetaxel and one of the novel endocrine agents is unknown, representing an unmet clinical need.

To address this unmet need, Prof. Ronald De Wit (Erasmus University Rotterdam, the Netherlands) presented results from the CARD trial, an open-label investigation of men with mCRPC who progressed 12 months on either abiraterone or enzalutamide and were then randomised to either cabazitaxel or the other anti-androgen therapy. The “European” dose of 25 mg/m² of cabazitaxel with G-CSF prophylaxis was given, as opposed to the FDA-approved dose of 20 mg/m². The primary endpoint was radiographic progression-free survival (PFS). Secondary endpoints were overall survival, PFS, and tumour response.

A median of 22 weeks or 7 cycles of cabazitaxel were administered, as opposed to 12.5 weeks of alternative anti-androgen. About 20% of patients in the cabazitaxel arm discontinued treatment due to treatment-related side effects, which was attributed to the total number of cumulative chemotherapy doses. More patients discontinued therapy in the alternative anti-androgen arm due to disease progression. Side effects were generally balanced between groups. Febrile neutropenia was only noted in 3.2% of patients.

The primary outcome was met, as cabazitaxel treatment offered statistically significant radiographic PFS benefit over alternative anti-androgen therapy (HR 0.54; P<0.001). Pre-planned subgroup analysis showed statistically significant benefit with cabazitaxel in almost all subgroups, and if not significant, data suggested a trend towards benefit with cabazitaxel.

Overall survival data also suggests a benefit for cabazitaxel. A benefit for other secondary outcomes such as PSA, pain response, and tumour size were also seen. Importantly, in a post-hoc analysis, the authors showed that regardless of which anti-androgen is administered first, the second anti-androgen has minimal efficacy, especially relative to cabazitaxel.

In summary, this study suggests that cabazitaxel should be a standard third line of care for patients who have received one of either abiraterone or enzalutamide and docetaxel chemotherapy.

Invited discussant Dr Silke Gillessen (Kantonsspital St. Gallen, Switzerland) pointed out that we still do not know what the impact of docetaxel in the castration-sensitive setting vs the castration-resistant setting is.

1. de Wit, R et al. ESMO Congress 2019. Abstract LBA13.
2. de Wit, R et al. 2019. New Engl J Med. doi:10.1056/nejmoa1911206.

Posted on 26 November, 201918 March, 2024