FDA approval was given to a new regimen of cabazitaxel (Jevtana) to treat men with metastatic castration-resistant prostate cancer who previously received a docetaxel-containing regimen. The approval is for 20 mg/m2 every 3 weeks in combination with prednisone. The agency approved a dose of 25 mg/m2 every 3 weeks in this patient population in 2010.
The approval is based on phase III results from the PROSELICA trial published earlier this year. That data showed that the lower-dose regimen was noninferior for overall survival (OS) and was associated with a similar safety profile.
Median OS for patients assigned to the 20 mg/m2 dose (C20) was 13.4 months versus 14.5 months for those assigned to the 25 mg/m2 dose (C25; hazard ratio [HR], 1.024). Based on the per-protocol population, the estimated median OS was 15.1 for the C20 group and 15.9 months for the C25 group (HR, 1.042; 97.78% CI, 0.886-1.224).
The one-sided 98.89% upper boundary of the confidence interval (UCI) of the HR was 1.184, which was less than the 1.214 noninferiority margin, thus satisfying the predefined criteria for noninferiority in the intent-to-treat population of patients.
Noninferiority was defined as maintenance of ≥50% of the OS benefit associated with C25 versus mitoxantrone in the TROPIC trial, with 95% CI. The UCI of the HR for C20 versus C25 could not exceed 1.214 under a one-sided 98.89% CI after interim analyses. Secondary endpoints included progression-free survival (PFS), prostate-specific antigen (PSA), tumor and pain responses and progression, health-related quality of life, and safety.
Median progression-free survival (PFS) was 2.9 months in the C20 arm verse 3.5 months in patients receiving C25 (HR, 1.099; 95% CI, 0.974-1.240). Researchers observed similar rates in each arm for tumor, PSA, and pain progression. The most frequent PFS events were PSA progression (C20, 39.8%; C25, 34.7%) and pain progression (C20, 25.8%; C25, 28.1%).
There was no significant difference in the tumor response rate in evaluable patients receiving C20 and C25 (18.5% vs 23.4%, respectively; nominal P = .1924). Median time to tumor progression was 9.0 months for patients receiving C20 and 9.3 months for patients receiving C25 (HR, 1.096; 95% CI, 0.902-1.331).
PSA response rates were significantly higher in the C25 arm, with 29.5% of C20 patients and 42.9% of C25 patients demonstrating a ≥50% decline in PSA from baseline (nominal P<.001). Median time to PSA progression was 6.8 months or longer for patients receiving C25 compared with 5.7 months in the C20 arm (HR, 1.195; 95% CI, 1.025-1.393).
The safety population consisted of 580 patients assigned to C20 and 595 assigned to C25 who received at least 1 dose of cabazitaxel. Patients in the C20 group received a median of 6 treatment cycles for a median duration of 18 weeks. Patients in the C25 group received a median of 7 treatment cycles for a median duration of 21 weeks.
Researchers observed no significant difference in the number of patients who experienced a pain response and the rate of pain progression was similar in the 2 groups. Median time to pain progression was 6.2 months for patients receiving C20 versus 6.4 months for patients assigned to C25, with a similar risk for pain progression in both groups (HR, 1.046; 95% CI, 0.874-1.251).
More patients receiving C25 had dose delays and reductions compared with patients receiving C20. The most common treatment-emergent adverse event (AE) leading to death was neutropenic sepsis (C20, 0.2%; C25, 0.5%). The most frequent nonhematologic treatment-emergent AEs possibly related to study treatment in both cabazitaxel groups were diarrhea, nausea, and fatigue.
More patients in the C25 arm experienced serious treatment-emergent AEs (30.5% vs 43.2%). Overall, 95 patients (16.4%) assigned to C20 discontinued treatment due to toxicity, along with 19.5% of the C25 cohort.
In the C20 group, 41.8% experienced grade ≥3 neutropenia compared with 73.3% of patients in the C25 group. Researchers observed grade ≥3 febrile neutropenia in 2.1% of the C20 group and 9.2% of the C25 group. Eleven patients (1.9%) in the C20 arm reported grade ≥3 hematuria versus 25 patients (4.2%) in the C25 arm. Incidence of grade ≥3 alopecia, fatigue, and neuropathy was low in both arms.
One-fifth of patients in the C25 arm reported grade 3/4 infections compared with 10% of patients assigned to the lower dose.
Deaths within 30 days of the last study drug dose (5.4% vs 3.8%), and early infection-related deaths within 30 days of the treatment initiation (1.3% vs 0.7%) were more common in the C25 arm. All of the early infection-related deaths occurred in patients older than 60 years of age.