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The investigational small molecule masitinib plus docetaxel resulted in a statistically significant 21% reduction in the risk of progression or death compared with placebo plus docetaxel in men with metastatic castration-resistant prostate cancer and baseline alkaline phosphatase levels of 250 IU/mL or less.
The investigational small molecule masitinib plus docetaxel resulted in a statistically significant 21% reduction in the risk of progression or death compared with placebo plus docetaxel in men with metastatic castration-resistant prostate cancer (mCRPC) and baseline alkaline phosphatase levels (ALP) of 250 IU/mL or less, according to findings from the primary analysis of the phase 3 Study AB12003 (NCT03761225) presented during the 2021 AUA Annual Meeting.1
In the targeted subgroup (n = 450), the overall primary progression-free survival (PFS) was 6.3 months (95% CI, 5.6-7.6) with masitinib plus docetaxel compared with 5.4 months (95% CI, 4.6-6.0) with placebo plus docetaxel (hazard ratio [HR], 0.79; 95% CI, 0.64-0.97; P = .027). The HRs for overall PFS stratified by LRT sensitivity (95% CI, 0.64-0.97; P = .0087) and by intention-to-treat (ITT) sensitivity (95% CI, 0.63-0.96; P = .027) were also 0.79.
No statistically significant PFS benefit was observed for the overall population irrespective of ALP. The overall primary PFS was 5.7 months (95% CI, 4.9-6.3) with masitinib/docetaxel vs 5.4 months (95% CI, 4.9-5.9) with placebo docetaxel (HR, 0.94; 95% CI, 0.81-1.10; P = .30).
“The combination of masitinib plus docetaxel may provide a new first-line treatment option for patients with mCRPC with low metastatic involvement,” lead study author Michel Pavic, MD, PhD, a professor of medicine in the Department of medicine at Université de Sherbrooke in Sherbrooke, Quebec, said in a presentation on the data.
Masitinib is an oral, small molecule agent directed toward mast cell and macrophage activity, which are key aspects of the tumor microenvironment and are associated with prostate cancer progression.
Previously reported data from the AB07004 trial demonstrated slowed disease progression with masitinib plus docetaxel in men with mCRPC, Pavic explained.
To be eligible for enrollment on the placebo-controlled, double-blind Study AB12003 trial, patients had to have chemotherapy-naïve, confirmed mCRPC and had progressed on previous abiraterone acetate (Zytiga) or were indicated for treatment with docetaxel. Patients had ECOG performance scores of 1 or less.
Study participants were randomized to first-line masitinib at a daily dose of 6.0 mg/kg in combination with intravenous docetaxel at a dose of 75 mg/m2 plus prednisone for up to 10 cycles or placebo plus docetaxel.
PFS by Prostate Cancer Clinical Trials Working Group 2 criteria served as the primary end point of the study. PFS comprised different variables, including radiographic progression by RECIST v1.1 criteria in the soft tissue and 2 new lesions confirmed 12 weeks apart in the bone; prostate-specific antigen (PSA) progression by at least a 25% increase in PSA above the nadir and at least a 2-ng/mL absolute increase confirmed 12 weeks apart; symptomatic progression of pain and analgesic by at least a 25% increase in Present Pain Intensity from baseline confirmed 12 weeks apart; or death.
Additionally, significant treatment effect was defined at an alpha level of 3.9% for the prespecified target subgroup, with the fallback procedure to conserve the overall alpha level at 5% for the overall population, Pavic said.
The primary analysis was performed on the overall population, as well as the targeted subgroup of patients with a lower risk of metastases with baseline ALP of 250 IU/mL or less.
In the overall cohort, the ITT population included 714 patients, the safety population included 712 patients, and the modified ITT (mITT) population included 712 patients. In the targeted subgroup, the ITT population, safety population, and mITT population included 451, 450, and 450 patients, respectively.
Further results from sensitivity analyses revealed that the 12-, 18-, and 24-month PFS rates were significantly improved with masitinib plus docetaxel compared with placebo plus docetaxel in the target subgroup population. The 12-month PFS rate was 32.0% with masitinib/docetaxel vs 19.6% with placebo/docetaxel (relative improvement, 1.6-fold; P = .0035). The 18-month PFS rates were 27.6% vs 14.6%, respectively (relative improvement, 1.9-fold; P = .0001). The 24-month PFS rates were 23.1% vs 12.0%, respectively (relative improvement, 1.9-fold; P = .0028).
Additionally, sensitivity analyses revealed that a greater treatment effect was observed with masitinib in patients with lower ALP levels, and therefore, less advanced metastatic disease. In patients with ALP of 200 IU/mL or less, the median PFS was 6.9 months (95% CI, 5.8-7.9) with masitinib/docetaxel (n = 178) vs 5.6 months (95% CI, 4.6-6.2) with placebo/docetaxel (n = 176; HR, 0.73; risk benefit percentage, 27%; P = .013). In patients with ALP of 150 IU/mL or less, the median PFS was 6.9 months (95% CI, 5.6-8.5; n = 134) vs 5.5 months (95% CI, 4.6-6.9; n = 133), respectively (HR, 0.63; risk benefit percentage, 37%; P = .001). In patients with ALP 100 IU/mL or less, the median PFS was 9.0 months (95% CI, 7.6-10.7; n = 59) vs 6.9 months (95% CI, 5.5-7.9; n = 72), respectively (HR, 0.53; risk benefit percentage, 47%; P = .002).
Regarding safety, “masitinib in combination with docetaxel only slightly increased the overall incidence rate ratio [IRR] of adverse [effects; AEs] with respect to placebo,” Pavic noted.
Moreover, the safety profile observed in this study was consistent with the known toxicities associated with masitinib, and included neutropenia, anemia, diarrhea, and skin reactions. No new safety signals were reported with the agent.
In the safety cohort, 96.6% of patients who received masitinib plus docetaxel (n = 355) vs 96.4% of patients who received placebo plus docetaxel (n = 357) experienced any-grade AEs (IRR, 1.0). Severe, grade 3 or 4 AEs were observed in 79.2% vs 73.1% of patients, respectively (IRR, 1.1).
AEs leading to death were reported in 5.4% vs 6.2% of patients, respectively (IRR, 0.9). Non-fatal serious AEs were observed in 27.6% vs 18.8% of patients, respectively (IRR, 1.5).
Treatment-emergent AEs that led to treatment discontinuation were experienced by 26.5% of patients who received masitinib/docetaxel compared with 18.5% of those who were given placebo/docetaxel (IRR, 1.4).
“The positive outcome of Study AB12003 provides further clinical evidence associating mast cells with the pathophysiology of mCRPC,” Pavic concluded.