Exposure-Response (E-R) analysis of efficacy and safety of niraparib/abiraterone acetate combination in patients with metastatic castration-resistant prostate cancer
Muriel Boulton (1), Anasuya Hazra (2*), Angela Lopez-Gitlitz (2), Ke Zhang (2), Hui Tian (2), Nahor Haddish-Berhane (2), Juan Jose Perez Ruixo (3), Alberto Russu (4)
(1) Janssen R&D, Belgium, (2) Janssen R&D, USA, (3) Janssen-Cilag Spain, Spain, (4) Janssen-Cilag SpA, Italy, *At the time of study conduct. Current affiliation: Regeneron, Tarrytown, NY
Introduction: Targeting the androgen receptor (AR) continues to be an important therapeutic approach in patients with metastatic castration-resistant prostate cancer (mCRPC). However, available evidence suggests that alterations in homologous recombination repair (HRR) genes, such as the breast cancer gene (BRCA), act as a second oncogenic driver and contribute to poor outcomes, resulting in earlier disease progression and higher risk of death. The niraparib/abiraterone acetate (AA) fixed-dose combination as dual-action tablet contains 2 active substances that target both oncogenic drivers: a hormonal therapy, AA, which targets the AR-axis, and a poly (adenosine diphosphate-ribose) polymerase inhibitor, niraparib, which targets HRR gene alterations including BRCA alterations.
Objectives: MAGNITUDE (EudraCT: 2017-003364-12) is a Phase 3 study that evaluated the efficacy and safety of the combination of niraparib with abiraterone acetate plus prednisone (AAP) compared with AAP plus placebo in subjects with mCRPC. The objectives of this analysis were to explore the relationship between niraparib exposure and the primary endpoint (radiographic progression-free survival, rPFS, by central review) in subjects with HRR gene alteration (Cohort 1) and with BRCA gene alterations and to explore the relationship between niraparib exposure and safety endpoints (Grade 3 or higher hematological toxicity [including thrombocytopenia, anemia, and/or neutropenia], nausea, hypertension, hypokalemia, fluid retention/edema, hepatotoxicity) in subjects with or without HRR gene alterations (Cohorts 1 and 2).
Methods: At the primary analysis, multivariate Cox regression models were used to characterize the relationship between niraparib exposure and rPFS, adjusted for the statistically significant prognostic factors (baseline prostate-specific antigen, lactate dehydrogenase, alkaline phosphatase levels, presence of visceral disease, and age). Furthermore, at the second interim analysis, multivariate logistic regression models were used to characterize the relationship between niraparib exposure and selected treatment-emergent adverse events (TEAEs) meeting the pre-defined criteria for application of E-R analysis (overall incidence ≥10% and significant difference between the incidences in the treatment groups based on a nominal p-value <0.05). The exposure metrics for the efficacy and safety analyses were respectively the individual average drug concentration (Cavg) and the individual AUC0-24h, both based on the post-hoc estimates from the final population pharmacokinetic model and scaled by the average daily dose up to the time of the first event of interest (rPFS event, TEAE, end of treatment, censoring date).
Results: The niraparib plus AAP combination of 200/1,000 mg showed a statistically significant reduction in the risk of radiographic progression or death compared with the placebo plus AAP combination (HR=0.729; 95% CI: 0.556, 0.956; p=0.0217). The multivariate Cox regression with niraparib Cavg categorized by quartiles adjusted for the prognostic factors for the All HRR population (N=414) resulted in a hazard ratio (HR) lower than 1 for all quartiles (HR=0.732, 0.486, 0.736, 0.823 in Q1 to Q4 respectively) and a lack of E-R relationship. Similar results were obtained in a subgroup analysis including only subjects with BRCA gene alterations (N=221). Therefore, differences in niraparib exposure within the evaluated dosing regimens are not expected to be associated with clinically relevant differences in rPFS for the All HRR population as well as the BRCA subgroup.
For the safety endpoints, only anemia met the pre-defined criteria, with an overall incidence of 21%, of which 35% were in the niraparib plus AAP group versus 8% in the placebo plus AAP group (N = 656). The other endpoints were reported in <10% of the subjects and/or with similar proportions between treatment groups. While there was an increased probability of experiencing Grade 3/4 anemia with increasing niraparib exposure, this was manageable with dose interruptions/reductions and supportive care, with only few subjects discontinuing study treatment due to anemia in MAGNITUDE.
Conclusions: The E-R analysis based on safety and efficacy data obtained in subjects with mCRPC in MAGNITUDE supports the adequacy of the intended clinical dose of 200 mg niraparib in combination with 1,000 mg AA mg. For niraparib related tolerability issues, the dose of niraparib can be reduced to 100 mg.