SUMMARY: The FDA on August 11, 2023, approved the fixed dose combination of Niraparib and Abiraterone acetate (AKEEGA®) with prednisone, for adult patients with deleterious or suspected deleterious BRCA-mutated Castration Resistant Prostate Cancer (mCRPC), as determined by an FDA-approved test. Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 288,300 new cases of Prostate cancer will be diagnosed in 2023 and 34,700 men will die of the disease.
The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPI), which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide) and ERLEADA® (Apalutamide). Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies.
DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HRR pathway. At least 15 genes are involved in the HRR pathway including BRCA1, BRCA2 and ATM genes. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. BRCA1 and BRCA2 are tumor suppressor genes and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Recently published data has shown that deleterious Germline and/or Somatic mutations in BRCA1, BRCA2, ATM, or other Homologous Recombination DNA-repair genes, are present in about 30% of patients with advanced prostate cancer, including metastatic CRPC. Patients with metastatic CRPC harboring BRCA alterations and other HRR gene alterations have poor outcomes and earlier resistance to commonly used systemic therapies.
The PARP (Poly ADP Ribose Polymerase), family of enzymes include, PARP1and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors trap PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in HRR genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death. PARP inhibitors have demonstrated significant activity in patients with prostate cancer and HRR gene alterations, with the greatest clinical benefit noted in BRCA1/2 mutation carriers. Niraparib (ZEJULA®) is a highly selective PARP-1 and PARP-2 inhibitor approved for several indications, including ovarian, fallopian tube, and primary peritoneal cancers. When given along with Abiraterone and Prednisone, the combination targets two oncogenic drivers in patients with metastatic CRPC (mCRPC), which include alterations in the Androgen Receptor axis and BRCA1/2 in the HRR pathway.
MAGNITUDE is a multicenter, multicohort, placebo-controlled, randomized, double-blind, Phase III study, prospectively designed as a precision medicine study to identify the specific population of patients who would most benefit from Niraparib with Abiraterone Acetate plus Prednisone, and potentially increase the likelihood of treatment success. This study involved 3 cohorts of patients: Cohort 1: Participants with mCRPC and HRR Gene Alteration. Cohort 2: Participants with mCRPC and No HRR Gene Alteration. Cohort 3 (Open-label): Participants with mCRPC
The present FDA approval was based on the safety and efficacy data from Cohort 1 group of patients with metastatic CRPC with HRR gene mutation. In this cohort, 423 patients (N=423) with HRR gene-mutated mCRPC were randomized (1:1) to receive Niraparib 200 mg orally once daily along with Abiraterone acetate 1,000 mg plus Prednisone 10mg daily, or placebo and Abiraterone acetate plus Prednisone daily. Patients with HRR positive biomarker included those with ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2 gene alterations. Approximately 53% had BRCA gene mutations. Patients were required to have a prior orchiectomy or be receiving GnRH analogues. Patients with mCRPC were eligible if they had not received prior systemic therapy in the mCRPC setting except for a short duration of prior Abiraterone acetate plus Prednisone (up to four months) and ongoing ADT. Patients could have received prior chemotherapy with Docetaxel or Androgen-Receptor (AR) targeted therapies in earlier disease settings. Randomization was stratified by prior Docetaxel, prior AR targeted therapy, prior Abiraterone acetate plus Prednisone, and BRCA status. The Primary endpoint of this trial was radiographic Progression Free Survival (rPFS) assessed by blinded Independent Central Review. Secondary endpoints included time to initiation of cytotoxic chemotherapy, time to symptomatic progression and Overall Survival.
The combination of Niraparib and Abiraterone with Prednisone significantly improved rPFS in all HRR-positive patients (HR=0.73; P=0.022). This improvement was most pronounced in patients with BRCA1/2 gene mutations and the median rPFS was 16.6 months versus 10.9 months (HR=0.53; P=0.0014), with a 47% reduction in the risk of disease progression. With additional median follow up at 24.8 months in the BRCA subgroup, rPFS by Independent Central Review demonstrated a consistent and clinically meaningful treatment benefit favoring Niraparib plus Abiraterone, with a median rPFS of 19.5 months, compared with 10.9 months for placebo plus Abiraterone and Prednisone. Additionally, in the BRCA gene mutated patients, an exploratory OS analysis demonstrated a median of 30.4 versus 28.6 months favoring the Niraparib combination (HR=0.79). Further there was a strong improvement in time to symptomatic progression and clinically meaningful improvement in time to initiation of cytotoxic chemotherapy in the Niraparib combination group. The most common Grade 3 Adverse Events were anemia and hypertension, and the Niraparib combination also maintained overall quality of life, compared to placebo plus Abiraterone and Prednisone.
It was concluded from this study that Niraparib in combination with Abiraterone and Prednisone significantly improved radiographic Progression Free Survival and other clinically relevant end points compared to placebo plus Abiraterone and Prednisone, in patients with BRCA1/2 gene altered metastatic Castration Resistant Prostate Cancer. The authors added that MAGNITUDE study enrolled the largest cohort of BRCA1/2-positive patients for the first line treatment of metastatic Castration Resistant Prostate Cancer to date, emphasizing the importance of identifying patients with these molecular alterations.
Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial. Chi KN, Sandhu S, Smith MR, et al. Annals of Oncology 2023;34:772-782.
