Third-line treatment with cabazitaxel extended progression-free survival and overall survival in men with metastatic castration-resistant prostate cancer in the CARD trial. These results provide the first evidence from a randomized phase III trial for a survival benefit with third-line therapy, and as such, they inform clinical practice. Late-breaking results from CARD were presented during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2019 and published online simultaneously in The New England Journal of Medicine.^1,2

Until now, the optimal sequencing of new agents available for metastatic castration-resistant prostate cancer has been unknown. This study provides level 1 evidence that after patients with the disease experience treatment failure on docetaxel and one of the newer androgen signaling–targeted inhibitors (ie, abiraterone or enzalutamide), cabazitaxel can extend their lives.

“Progression-free survival, tumor responses, and pain responses all favored cabazitaxel.”

— Ronald de Wit, MD, PhD

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“CARD met its primary endpoint. Cabazitaxel more than doubled progression-free survival and reduced the risk of death by 36% vs abiraterone or enzalutamide. All other secondary endpoints favored cabazitaxel. Radiographic progression-free survival remained superior regardless of abiraterone/enzalutamide sequence. These results support the use of cabazitaxel over abiraterone or enzalutamide in this setting. This study is practice-changing,” stated Ronald de Wit, MD, PhD, of Erasmus University Medical Center, Rotterdam, The Netherlands.

Docetaxel, enzalutamide, and abiraterone have all shown an overall survival benefit in metastatic castration-resistant prostate cancer, but a common clinical dilemma is how best to sequence these drugs. Studies suggest that the chances of achieving a response are low after treatment failure on abiraterone or enzalutamide when the other of the two drugs is used. Cabazitaxel retains the potential for producing a response after disease progression on either of these newer androgen receptor inhibitors.

“Patients may not respond to abiraterone after treatment with enzalutamide, and vice versa, yet this sequence is widely used in clinical practice,” Dr. de Wit noted.

Study Details

Between 2015 and 2018, the multicenter CARD trial enrolled men with metastatic castration-resistant prostate cancer that has progressed within 12 months of either enzalutamide or abiraterone therapy, before or after treatment with docetaxel. Depending on which androgen receptor inhibitor men received previously, they were randomly assigned to receive cabazitaxel plus prednisone (n = 129) or either abiraterone plus prednisone or enzalutamide (n = 126).

The primary endpoint was radiographic progression-free survival. Secondary endpoints included overall survival plus progression-free survival, prostate-specific antigen (PSA) response, tumor response, pain response, time to a symptomatic skeletal event, safety, health-related quality of life, and biomarker analysis.

Patient characteristics were well balanced between the two treatment groups. Median age was 70 years, and about 30% were aged 75 or older. Two-thirds of patients had pain at study entry. Prior choice of the androgen signaling–targeted inhibitor and the sequence with docetaxel (before or after) were evenly distributed and comparable between arms at randomization. The median duration of prior enzalutamide or abiraterone treatment was 7.5 months.

The median duration of study treatment was 22 weeks for cabazitaxel recipients vs 12.5 weeks in the control arm. At the time of data cutoff, 95% of patients in both arms discontinued treatment. More patients in the control arm discontinued treatment due to disease progression (71% vs 43.7% in the cabazitaxel arm). More treatment discontinuations were reported due to adverse events in the cabazitaxel arm: 19.8% vs 8.9% for controls, in part related to the longer exposure.

Key Findings

In the primary analysis, cabazitaxel reduced the risk of radiographic disease progression by 46% compared with controls (P < .0001). Median radiographic progression-free survival was 8.0 months on cabazitaxel vs 3.7 months on abiraterone or enzalutamide. A preplanned analysis showed that all subgroups had a consistent progression-free survival with cabazitaxel. Median overall survival was 13.6 months on cabazitaxel and 11 months on abiraterone or enzalutamide.

“There was no indication that patients who had received docetaxel in between the two lines of abiraterone and enzalutamide did any better,” Dr. de Wit said. “An exploratory analysis found that the sequence of androgen signaling–targeted inhibitors did not matter; the hazard ratio for the sequence of enzalutamide after abiraterone and docetaxel was 0.57.”

“Progression-free survival, tumor responses, and pain responses all favored cabazitaxel,” he stated. A confirmed PSA response was seen in 35.7% of the cabazitaxel am vs 13.5% of controls (P = .0002); objective tumor response rates were 36.5% vs 11.5%, respectively (P = .004); pain response rates were 45% vs 19.3%, respectively (P < .0001); and median time to symptomatic skeletal event was not yet reached vs 16.7 months, respectively (P = .05).

The rates of adverse events, grade 3 or higher adverse events, and serious adverse events were similar in the two treatment arms. Deaths were mainly due to disease progression. The rate of grade 3 or higher infections was 7% in both arms; febrile neutropenia occurred in 3.2% of the cabazitaxel arm vs 0% in controls. All patients receiving cabazitaxel were given prophylactic granulocyte colony-stimulating factor. 

DISCLOSURE: Dr. de Wit is an advisor/consultant for and has received speakers fees or research funding from Janssen, Sanofi, Merck, Bayer, Clovis, and Roche.

REFERENCES

1. de Wit R, Kramer G, Eymard J-C, et al: CARD: Randomized, open-label study of cabazitaxel vs abiraterone or enzalutamide in metastatic castration-resistant prostate cancer. ESMO Congress 2019. Abstract LBA13. Presented September 30, 2019.

2. de Wit R, de Bono J, Sternberg CN, et al: Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. September 30, 2019 (early release online).