AB Science announced that both the FDA and EMA have authorized a confirmatory phase 3 trial of masitinib in metastatic castrate-resistant prostate cancer (mCRPC), marking a significant regulatory milestone for the protein kinase inhibitor. The study, designated AB22007, will employ biomarker-driven patient selection to target the population most likely to benefit from treatment.
Professor Olivier Hermine, MD, President of the Scientific Committee of AB Science and member of the Académie des Sciences in France, emphasized the significance of this development: "The authorization of our confirmatory Phase 3 study by both the FDA and EMA represents a critical milestone for masitinib in metastatic castrate-resistant prostate cancer. With a validated biomarker guiding patient selection, this trial has the potential to establish the first targeted combination with docetaxel in nearly two decades for mCRPC."
Study Design and Patient Population
Study AB22007 is designed as a prospective, multicenter, randomized, double-blind, placebo-controlled phase 3 trial with two parallel groups. The study will evaluate the efficacy and safety of docetaxel (IV 75 mg/m² plus prednisone for up to 10 cycles) combined with masitinib 6.0 mg/kg/day versus docetaxel plus placebo in mCRPC patients.
The trial will enroll 600 patients with confirmed mCRPC who are eligible for docetaxel treatment and possess a biomarker indicative of less advanced metastatic disease, as measured by baseline alkaline phosphatase levels. Patients will be randomized 1:1 between treatment arms, with the primary endpoint being radiographic progression-free survival (rPFS) and overall survival as the first secondary endpoint.
Addressing Unmet Medical Need
Masitinib is positioned for use in combination with docetaxel as a treatment for mCRPC patients eligible for docetaxel, administered directly following resistance or relapse after metastatic hormone-sensitive prostate cancer treatments. Despite docetaxel's approval almost 20 years ago, there is currently no drug registered for use in combination with this standard of care treatment in patients who have relapsed on hormone treatments.
The medical need is substantial, with metastatic prostate cancer representing a significant challenge despite high survival rates for localized disease. The 5-year survival rate for metastatic prostate cancer is approximately 30%. Up to 20% of men who undergo state-of-the-art treatment for prostate cancer will develop CRPC within 5 years, and at least 84% of these will have metastases at the time of CRPC diagnosis.
Prostate cancer is the most common cause of cancer in men, with 137.9 new cases per 100,000 men per year. The estimated prevalence of people living with prostate cancer is 113 per 100,000, with approximately 15% of patients having mCRPC eligible for chemotherapy. This translates to a population of around 75,000 patients in the EU and 50,000 in the USA who are eligible for chemotherapy.
Biomarker Validation and Previous Trial Results
The confirmatory trial builds on results from study AB12003, which demonstrated that alkaline phosphatase (ALP) serves as a predictive biomarker for masitinib response in mCRPC. AB12003 was a prospective, placebo-controlled, double-blind, randomized phase 3 trial evaluating masitinib (6.0 mg/kg/day) in combination with docetaxel as a first-line treatment for mCRPC.
The study enrolled 712 patients in the overall cohort, with primary analysis performed on 450 patients in a pre-specified targeted subgroup defined as patients with baseline ALP levels ≤250 IU/L. The primary endpoint was progression-free survival using PCWG2 definition.
Results showed that masitinib plus docetaxel conferred a significant PFS benefit in mCRPC patients with ALP ≤250 IU/L, with a hazard ratio of 0.79 [0.64;0.97] (p=0.0087), corresponding to a 21% reduction in risk of progression relative to control. The 12-, 18-, and 24-month PFS rates showed significant improvement in favor of masitinib plus docetaxel relative to control: 1.6-fold (p=0.0035), 1.9-fold (p=0.0001), and 1.9-fold (p=0.0028), respectively.
Biomarker Correlation and Treatment Effect
A progressively greater masitinib treatment effect was observed for lower baseline ALP levels, indicating less advanced metastatic disease. Patients with ALP ≤100 IU/L showed a significant 47% reduced risk of progression with a hazard ratio of 0.53 (p=0.002). The efficacy and response of masitinib correlated directly with ALP levels, with the biomarker measuring the involvement of metastasis in bones and liver.
The use of ALP as a biomarker for the confirmatory phase 3 study has been validated by both FDA and EMA. When used sufficiently early, masitinib in combination with docetaxel was able to slow down the progression of metastatic cancer even when resistant to hormone treatments.
Safety Profile and Historical Context
The masitinib plus docetaxel safety profile was acceptable compared to control, consistent with the known masitinib profile and with no new safety signals observed. This represents a notable achievement given the historically high failure rate of trials studying combinations of docetaxel and new targeted agents, with study AB12003 being a rare example of a phase 3 clinical trial that showed improvement in progression-free survival for masitinib in combination with docetaxel.
Patent Protection
Based on the results from the AB12003 study, AB Science filed a patent application relating to methods of treating mCRPC with masitinib. The European Patent Office has granted this patent (EP4175639), providing protection until 2042 for masitinib and related compounds for treatment of mCRPC in the patient subpopulation with low metastatic involvement as measured by baseline alkaline phosphatase levels. Counterpart patent applications have also been filed in other major international markets, including the United States.
