New Standard in Third-Line Metastatic CRPC

BARCELONA — Switching to cabazitaxel (Jevtana) in lieu of another androgen receptor-signaling inhibitor improved survival in men with metastatic castration-resistant prostate cancer (CRPC) who progressed on docetaxel and one of the newer androgen-blocking agents, the phase III CARD trial found.

Among over 250 patients whose response to abiraterone (Zytiga) or enzalutamide (Xtandi) was less than a year, the radiographic progression-free survival (PFS) was 8.0 months for those who went on to cabazitaxel versus 3.7 months in those treated with the opposite anti-androgen (HR 0.54, 95% CI 0.40-0.73), and all subgroups appeared to benefit, reported Ronald de Wit, MD, PhD, of Erasmus Medical Center in Rotterdam, the Netherlands.

“The superiority of cabazitaxel also translated into a survival benefit,” he said during the presidential symposium of top abstracts at the European Society for Medical Oncology (ESMO) annual meeting. Results of the study were simultaneously published in the New England Journal of Medicine.

Men enrolled on the cabazitaxel arm had a median overall survival (OS) of 13.6 months, as compared with 11.0 months for those on the control arm of abiraterone or enzalutamide (HR 0.64, 95% CI 0.46-0.89), this despite the fact that one-third of patients in the control arm crossed over to cabazitaxel.

“These results support the use of cabazitaxel over abiraterone or enzalutamide in this setting,” de Wit added. “This can be considered practice-changing.”

Other secondary endpoints — PFS, rates of prostate-specific antigen (PSA) and tumor response, and reductions in pain — all significantly favored cabazitaxel:

• PFS: 4.4 vs 2.7 months (P<0.001)
• PSA response: 35.7% vs 13.5% (P<0.001)
• Tumor response: 36.5% vs 11.5% (P=0.004)
• Pain reduction: 45.0% vs 19.3% (P<0.001)

“Patients may not respond to abiraterone after progressing on prior enzalutamide and vice versa, yet the crossover between these two compounds is widely used both in Europe as well as in the United States,” explained de Wit. “Cabazitaxel, however, retains activity in patients progressing on prior docetaxel, abiraterone, or enzalutamide.”

“Until now we had no prospective randomized trials for third-line treatment,” said ESMO discussant Silke Gillessen, MD, of the University of Manchester in England.

“The statistics for the trial were very ambitious, but the results were even better,” she said. “The results of the CARD trial fit well with the hypothesis that patients with a short-ish response to endocrine treatment profit more from a cytotoxic treatment than from a next line of endocrine treatment.”

Gillessen agreed that the results offer clinicians a new standard of care in fit patients with metastatic CRPC.

“And the nice thing about it is you can go home from ESMO and you can adjust to that new standard because cabazitaxel is already approved,” she said.

Gillessen also pointed to the fact that in the U.S., the FDA has changed the recommended dose of cabazitaxel based on findings of the PROSELICA trial showing that a cabazitaxel dose of 25 mg/m² was noninferior to 20 mg/m² in terms of OS, and was less toxic.

A post-hoc analysis for the primary endpoint of radiographic PFS showed that the cabazitaxel arm performed better regardless of whether patients had received abiraterone after enzalutamide and docetaxel (HR 0.44, 95% CI 0.29-0.67) or enzalutamide after abiraterone and docetaxel (HR 0.57, 95% CI 0.57-0.90).

Rates of adverse events between the cabazitaxel and control groups were similar for any grade AEs (98.4% vs 94.4%), grade 3/4 AEs (56.3% vs 52.4%), and serious AEs (38.9% vs 38.6%). While more than twice as many men on cabazitaxel discontinued treatment for toxicity, at 19.8% compared with 8.9% for those on the anti-androgens, de Wit noted that this was due to longer treatment exposure. Median treatment duration was 22 versus 12.5 months in the two groups, respectively. Treatment-emergent deaths, largely due to disease progression in the control arm, were numerically lower with cabazitaxel (5.6% vs 11.3%).

The CARD study randomized 255 men who progressed within 1 year of treatment with docetaxel and either abiraterone or enzalutamide. In the investigational arm, 129 patients received 25 mg/m² cabazitaxel every 3 weeks along with prednisone and granulocyte colony-stimulating factor. In the control group, 126 patients received whichever anti-androgen they hadn’t yet been exposed to, at daily doses of 1,000 mg for abiraterone and 160 mg for enzalutamide.

Patient characteristics and biology were well balanced between the two arms. Median age at enrollment was slightly younger in the cabazitaxel arm (age 70) compared with the abiraterone/enzalutamide arm (age 71), but had a greater proportion of men ages ≥75 (34.9% vs 27.0%, respectively). Pain was reported in roughly two-thirds of each group. The cabazitaxel group had slightly lower rates of metastatic disease at diagnosis (38.0% vs 47.6%) and Gleason scores of 8-10 (56.6% vs 64.3%).

Stratification factors included ECOG performance status (0-1 vs 2) and timing of initial anti-androgen treatment (either before or after docetaxel). And while de Wit noted that of “special interest” was the time to progression on the initial androgen receptor-signaling inhibitor (<6 vs 6-12 months), both of these groups appeared to benefit more from cabazitaxel. Median duration of response to prior abiraterone or enzalutamide was about 8 months in the two groups.