Cabazitaxel Emerges as Third-Line Standard for Metastatic CRPC

Ronald de Wit, MD, PhD

Men who received cabazitaxel (Jevtana) as a third-line systemic agent for metastatic castration-resistant prostate cancer (mCRPC) had a significant reduction in radiographic disease progression, leading to a significant increase in overall survival (OS), a randomized trial showed.^1,2

The median time to progression doubled with cabazitaxel, as compared with abiraterone acetate (Zytiga) or enzalutamide (Xtandi), at 8.0 versus 3.7 months, respectively. After a median follow-up of 9.2 months, the median OS was 13.6 months with cabazitaxel and 11.0 months among patients who received either of the androgen signaling inhibitors.

Men treated with cabazitaxel had significantly less pain and fewer skeletal clinical events, as reported at 2019 ESMO Congress.

“[The trial] met its primary objective and reduced the risk of death by 36% versus abiraterone or enzalutamide,” said Ronald de Wit, MD, PhD, of Erasmus University Medical Center in Rotterdam, the Netherlands. “Radiographic progression-free survival (rPFS) remained superior regardless of the abiraterone/enzalutamide sequence. These results support the use of cabazitaxel over abiraterone or enzalutamide in this setting.”

The findings were published simultaneously in the New England Journal of Medicine.

Docetaxel, cabazitaxel, abiraterone, and enzalutamide have all demonstrated survival benefits in mCRPC. Studies have shown that patients might not respond to abiraterone after progression with enzalutamide and vice versa, said de Wit. Cabazitaxel retains activity after progression on prior docetaxel or either of the androgen signaling inhibitors.

That background provided the rationale for the multicenter, randomized CARD trial, which compared the efficacy and safety of cabazitaxel versus abiraterone or enzalutamide in men with mCRPC previously treated with docetaxel and either of the androgen signaling inhibitors.

The principal inclusion criterion was mCRPC that progressed within 12 months on an androgen signaling inhibitor before or after treatment with docetaxel. Investigators randomized patients to cabazitaxel plus prednisone or to abiraterone plus prednisone or enzalutamide, depending on which androgen signaling inhibitor a patient received previously.

The primary endpoint was rPFS. OS was a key secondary endpoint, along with PFS, PSA response, and tumor response. Other secondary endpoints included pain response, time to symptomatic skeletal event, safety, health-related quality of life (HRQoL), and biomarker analyses.

Data analysis comprised 255 randomized patients, who had a median age of 70. About 30% of the patients were 75 or older. Baseline characteristics were balanced, including the sequence of prior therapies. In the cabazitaxel arm, 55.8% of patients had received enzalutamide, whereas the majority in the control arm had received abiraterone (53.2%). Median duration of prior androgen-signaling targeted therapy was 7 to 8 months.

Baseline laboratory values included median PSA of about 60 ng/mL, hemoglobin of 121 to 122 g/L, alkaline phosphatase of 122 to 132 IU/L, lactate dehydrogenase of about 250 IU/L, and neutrophil to lymphocyte ratio of 3.37 to 3.38.

Median duration of treatment was longer with cabazitaxel (22.0 vs 12.5 weeks), and median cycles of therapy was 7 with cabazitaxel and 4 with the androgen signaling inhibitors. More patients in the control group had at least 1 cycle of therapy with dose reduction (37.9% vs 21.4%).

Most patients in the control group discontinued treatment because of disease progression (71.0% vs 43.7%), whereas more in the cabazitaxel arm discontinued because of adverse events (19.8% vs 8.9%), investigator decision (16.7% vs 4.0%), and patient decision (9.5% vs 3.2%).

The primary analysis showed that cabazitaxel reduced the risk of radiographic progression by 46% versus the control group (P <.0001). A preplanned subgroup analysis showed a consistent advantage for treatment with cabazitaxel.

The survival analysis showed a median OS of 13.6 months with cabazitaxel and 11.0 months with the androgen-signaling targeted drugs. The difference translated into a hazard ratio of 0.64 (P = .0078).

Beyond OS, secondary endpoints consistently favored cabazitaxel:

• Confirmed PSA response — 35.7% vs 13.5% (P = .0002)
• Objective tumor response — 36.5% vs 11.5% (P = .004)
• Pain response — 45.0% vs 19.3% (P <.0001)
• Time to skeletal event — NR vs 16.7 months (HR, 0.59; P = .05)

Cabazitaxel-treated patients (n = 56) had improved rPFS as compared with enzalutamide (n = 66), 7.4 vs 4.8 months (HR, 0.57) and with abiraterone (n = 72 vs n = 60; 8.2 vs 3.4 months; HR, 0.44).

Adverse events, grade ≥3 adverse events, and serious adverse events occurred in a similar proportion of patients in the cabazitaxel and control groups.

Invited discussant Silke Gillessen, MD, of the University of Manchester, described the CARD trial as well designed and addressing an unmet clinical need, with a patient population representative of patients seen in the clinic.

“The current treatment landscape is that fit patients should have docetaxel and abiraterone or enzalutamide at some stage,” she said. “A subgroup of patients can derive benefit from PARP inhibitors, and another subgroup can derive benefit from pembrolizumab.

“The new information provided by this trial is that cabazitaxel should be considered a new standard of care for third-line for fit patients with progressive disease on prior androgen receptor therapy in less than 12 months.”

References

1. De Wit R, Kramer G, Eymard J-C, et al. - CARD: Randomized, open-label study of cabazitaxel (CBZ) vs abiraterone (ABI) or enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC). Presented at ESMO 2019; September 27-October 1, 2019; Barcelona, Spain. LBA13.
2. De Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer [published online September 30, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1911206.

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