SUMMARY: It is estimated that in the United States, approximately 19,880 women will be diagnosed with ovarian cancer in 2022 and 12,810 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Approximately 85% of all ovarian cancers are epithelial in origin, and approximately 70% of all epithelial ovarian cancers are High-Grade Serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5 year Overall Survival rate of about 20-30%.
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 are tumor suppressor genes and they recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination 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 HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1 and BRCA2 genes. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers 15% of ovarian cancers, in addition to other cancers such as colon and prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic).
The PARP (Poly ADP Ribose Polymerase) family of enzymes includes PARP1 and 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 traps PARP onto DNA at sites of single-strand breaks, thereby preventing their repair and generate double-strand breaks. These breaks cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death.
RUBRACA® is an oral, small molecule PARP inhibitor, developed for treatment of ovarian cancer associated with Homologous Recombination DNA repair deficiency (HRD). With regards to ovarian cancer, RUBRACA® is presently approved by the FDA for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a Complete or Partial Response to platinum-based chemotherapy.
ATHENA is an international, multicenter, randomized, double-blind, placebo-controlled, Phase III trial, which evaluated first-line maintenance treatment for patients with newly diagnosed advanced ovarian cancer. ATHENA was designed to evaluate RUBRACA® first-line maintenance treatment in a broad group of patients, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of Homologous Recombination Deficiency (HRD), or high-risk clinical characteristics such as residual disease. ATHENA study has two separate and fully independently powered comparisons evaluating RUBRACA® monotherapy (ATHENA–MONO) and RUBRACA® plus Nivolumab (ATHENA–COMBO), as maintenance treatment in this patient population. The authors herein reported the efficacy and safety results from the ATHENA–MONO comparison of RUBRACA® maintenance treatment versus placebo.
In the ATHENA-MONO trial, patients with Stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to 4-8 cycles of first-line platinum-doublet chemotherapy, were randomly assigned 4:1 to receive RUBRACA® 600 mg orally twice daily (N=427) or placebo. Treatment was continued for 24 months or until disease progression or unacceptable toxicity. Patients were stratified by HRD test status, residual disease after chemotherapy, and timing of surgery (primary surgery versus interval debulking). The median age was 61 years, majority of the patients (78%) did not have a BRCA mutation. Patients were stratified by HRD classification (BRCA wild-type/LOH (Loss of Heterozygosity) high-16% or more, BRCA wild-type/LOH low-less than 16%, and BRCA wild-type/LOH indeterminate). The Primary end point of investigator-assessed Progression Free Survival (PFS) was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/LOH high tumor), and then in the Intent-To-Treat (ITT) population. Secondary end points included Overall Survival (OS), investigator-assessed Objective Response Rate (ORR) in patients with measurable disease at baseline and Duration of Response (DOR) for patients with investigator-assessed confirmed radiographic Complete Response (CR) or Partial Response (PR). The median duration of follow was 26 months.
The median PFS in the HRD population was 28.7 months with RUBRACA® maintenance group compared to 11.3 months with placebo (HR=0.47; P=0.0004). In the Intent to Treat (ITT) population, the median PFS was 20.2 months in the RUBRACA® group versus 9.2 months in the placebo group (HR=0.52; P<0.0001). At 24 months, 45% of RUBRACA®-treated patients in the ITT population were progression-free compared with 25.4% with placebo. In the HRD negative population, the median PFS was 12.1 months in the RUBRACA® group versus 9.1 months in the placebo group (HR=0.65). Exploratory subgroup analyses of PFS in the ITT population showed that there was greater clinical benefit with RUBRACA® compared to placebo among all subgroups, including BRCA-mutant, BRCA wild-type/LOH high, and BRCA wild-type/LOH low (HRD-negative).
Among RUBRACA®-treated patients with measurable disease at baseline, the ORR, was 58.8% in the HRD population and 48.8% in the ITT population. Among the placebo-treated patients, the ORR was 20% in the HRD population and 9.1% in the ITT population. The median Duration of Response in the HRD and ITT populations for RUBRACA®-treated responders versus the placebo-treated responders respectively, was 16.7 months versus 5.5 months and 22.1 months versus 5.5 months. The Overall Survival results were immature at the time of the data cutoff. The most common Grade 3 or more adverse events in the RUBRACA® group were anemia (29%) and neutropenia 15%).
The authors concluded that in the ATHENA-MONO trial, RUBRACA® monotherapy is an effective first-line maintenance option that provides clinical benefit to a broad population of patients with newly diagnosed ovarian cancer, regardless of BRCA mutation and HRD status.
A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA–MONO/GOG-3020/ENGOT-ov45). Monk BJ, Parkinson C, Lim MC, et al. DOI: 10.1200/JCO.2022.40.17_suppl.LBA5500 Journal of Clinical Oncology 40, no. 17_suppl (June 10, 2022) LBA5500-LBA5500. Published online June 08, 2022.