Cabazitaxel aces CARD

Men with metastatic castration-resistant prostate cancer (mCRPC) derived significantly greater clinical benefit from cabazitaxel vs the androgen receptor-targeted agents (ARTA) abiraterone or enzalutamide, according to the results of the CARD* trial presented at ESMO 2019.

“Cabazitaxel more than doubled the radiographic progression-free survival (rPFS) vs [the ARTAs],” said Dr Ronald de Wit from Erasmus University Medical Center in Rotterdam, the Netherlands. The median PFS for the cabazitaxel arm was 8.0 months as opposed to 3.7 months for the ARTA arm after a median follow-up of 9.2 months. This translated to a significantly lower rate of rPFS or death with cabazitaxel vs ARTA (hazard ratio [HR], 0.54, 95 percent confidence interval [CI], 0.40–0.73; p<0.001). [ESMO 2019, abstract LBA 13]

All key secondary endpoints also favoured cabazitaxel over ARTAs (HR, 0.64; p=0.008 [median overall survival], HR, 0.52; p<0.001 [median PFS], 35.7 percent vs 13.5 percent; p<0.001 [prostate-specific antigen response], and 36.5 percent vs 11.5 percent; p=0.004 [tumour response]).

The study involved 255 men (median age 70 years) with mCRPC who had previously received docetaxel and progressed within 12 months while receiving abiraterone or enzalutamide. Participants were randomized 1:1 to receive intravenous cabazitaxel (25 mg/m² of body surface area 1 hour every 3 weeks) plus oral prednisone 10 mg daily and granulocyte colony-stimulating factor (GCSF), or the alternative inhibitor (abiraterone 1,000 mg once daily plus oral prednisone 5 mg twice daily or enzalutamide 160 mg once daily). [N Engl J Med 2019;doi:10.1056/NEJMoa1911206]

“Patients may not respond to abiraterone after progressing on prior enzalutamide and vice versa, yet the crossover between these two compounds is widely used … Cabazitaxel, however, retains activity in patients progressing on prior docetaxel, abiraterone, or enzalutamide,” explained de Wit. This retention could be attributed to the greater intratumoural penetration with cabazitaxel compared with docetaxel, especially in treatment-resistant tumours. [Eur Urol 2015;68:228-235; Eur Urol 2017;71:656-664; Prostate 2016;76:927-936]

The impact of sequence, crossovers

In view of evidence suggesting the influence of ARTA sequencing in PFS, [Int J Urol 2017;24:441-448; Eur Urol Oncol 2018;1:467-475] the investigators conducted a post hoc analysis which showed the superiority of cabazitaxel over abiraterone (median rPFS, 8.2 vs 3.4 months; HR, 0.44) or enzalutamide (median rPFS, 7.4 vs 4.8 months; HR, 0.57) regardless of the sequence of the previous ARTA. “[Although] some believe that enzalutamide after abiraterone is effective … [the HR suggests] that this sequence did not perform any better,” he continued.

It is important to note that despite the crossover to cabazitaxel of nearly a third of ARTA recipients, there was a survival benefit, de Wit pointed out. Another notable aspect is the palliative radiotherapy received by 22 percent of ARTA recipients. “[While] some of these patients would have become too frail to receive cabazitaxel … [the radiotherapy] did not confound the survival benefit …  [These results] clearly indicate that we should not lose the window of opportunity … [We should] choose the right [drug] at the right time,” underscored de Wit.

Favourable safety profile

The cabazitaxel and ARTA arms had similar incidences of any grade ≥3 adverse events (AEs, 56.3 percent vs 52.4 percent) and serious AEs (38.9 percent vs 38.7 percent). ARTA recipients had a higher incidence of AEs leading to death than those who received cabazitaxel mainly due to disease progression (11.3 percent vs 5.6 percent).

Of note is the incidence of febrile neutropenia with cabazitaxel, which was only 3.2 percent at any cycle notwithstanding the 25-mg dose and primary GCSF prophylaxis. “[This finding suggests] that cabazitaxel was a very well-tolerated regimen,” said de Wit.

Taken together, these findings support the use of cabazitaxel over abiraterone or enzalutamide in mCRPC. “[Our findings] will affect treatment decisions [and can therefore] be considered practice changing,” concluded de Wit.

New third-line standard of care?

“[CARD] was a well-designed trial addressing an unmet clinical need. The patient population is representative of many of our patients that we see in the clinic,” said discussant Dr Silke Gillessen from Kantonsspital St Gallen in St Gallen, Switzerland.

The findings have clearly brought some light on the potential of cabazitaxel as a new standard of care in the third-line setting in this patient subgroup, added Gillessen. “[Moreover,] we should try to resist chemophobia,” she said, noting the favourable toxicity profile of cabazitaxel that was reflected in the study.

It would be worth looking into the sufficiency of the 20-mg dose as the 25-mg dose might not be necessary, noted Gillessen. Further studies should also investigate whether the findings may be extrapolated to castration-sensitive patients receiving the same agents. “This is important because that is where the field has moved,” she said. Future trials should also determine the optimal treatment for patients who are unfit for chemotherapy and for those who benefit from initial ARTA lasting >1 year, she added.