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By Melissa Moffitt, MD
Gynecologic Oncologist, Assistant Professor, Department of OB/GYN, Oregon Health & Science University, Portland
Dr. Moffitt reports no financial relationships relevant to this field of study.
SYNOPSIS: The PRIMA study is a randomized, double-blind, multi-institutional, international phase 3 trial testing the PARP inhibitor niraparib against placebo after first-line standard treatment with platinum-based chemotherapy for newly diagnosed ovarian cancer.
SOURCE: González-Martín A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2019 Sept. 28. doi: 10.1056/NEJMoa1910962. [Epub ahead of print].
Standard treatment (ST) for newly diagnosed advanced epithelial ovarian cancer generally consists of tumor reductive surgery and platinum-based chemotherapy. This treatment usually is not curative, since 85% of patients experience recurrence.
Poly (ADP-ribose) polymerase (PARP) is a group of enzymes involved in DNA repair. Currently multiple drugs on the market target and inhibit PARP enzymes’ ability to repair damaged DNA. If PARP is impaired or inhibited, the cell ultimately dies. PARP inhibition (PARPi) has emerged as one of the new targeted treatments used in cancer care. Until this point, it also has been considered “personalized medicine,” as PARPi has been used as maintenance treatment after initial ST primarily in two sets of women: those with a germline breast cancer gene (BRCA) mutation; and those without a germline BRCA mutation, but with ovarian cancer that has developed a somatic BRCA mutation or BRCA-related mutation.
BRCA genes rely on other genes to function. When there are somatic mutations in tumor BRCA or the genes that BRCA requires to function, the BRCA gene cannot act as a tumor suppressor. When ovarian cancer tumors express somatic BRCA mutations or mutations in the genes BRCA relies on, this is referred to as homologous-recombination deficiency (HRD). Currently, for a patient to be a candidate for PARPi at initial diagnosis after ST, she must have proven HRD. Thus, nearly all advanced-stage epithelial ovarian cancer patients undergo germline BRCA mutation testing and tumor molecular analysis. In women with HRD, PARPi after initial ST lengthens progression-free survival 36 months compared to placebo, with a hazard ratio (HR) for disease progression or death of 0.30 (95% confidence interval [CI], 0.23-0.41).1 In the same study, PARPi after initial ST not only lengthened the initial remission, but after recurrence, the progression-free survival after second-line treatment also was longer than in those who received placebo, showing that PARPi has a sustained effect. PARPi gives some ovarian cancer patients a very realistic hope for longer life.
Some studies have suggested that PARPi after ovarian cancer recurrence and second-line treatment benefits a wider spectrum of ovarian cancer patients than just those with BRCA mutations or HRD. In the PRIMA study, González-Martín and colleagues evaluated PARPi in patients with and without HRD but at the time of initial diagnosis, after ST. The authors enrolled 733 women with an initial diagnosis of advanced-stage, high-grade serous and endometrioid ovarian cancers after those patients had achieved a complete or partial response to ST. Many of the patients enrolled were at high risk for early recurrence (suboptimal tumor reductive surgery, inoperable cancer, stage IV disease, etc.), so shorter than usual progression-free survivals were expected.
All the enrolled patients were randomized 2:1 to receive PARPi (niraparib) or placebo. All of the patients’ tumors were molecularly analyzed; half were found to have HRD. The randomization was double-blinded and stratified according to HRD status and whether patients received neoadjuvant chemotherapy. The patients took their oral treatments daily, starting within three months of finishing initial standard ovarian cancer treatment and continuing until cancer progression or 36 months. The patients were assessed every three months with imaging until the oral medication was discontinued. The primary endpoints were progression-free survival in patients with HRD and progression-free survival in all enrolled patients. As expected, the women with HRD had great benefit from PARPi: The median progression-free survival in patients with HRD who received niraparib was 22 months vs. 10 months in those who received placebo, with HR, 0.43 (95% CI, 0.31-0.59) for disease progression or death. Importantly, those without HRD also benefited from PARPi, with a median progression-free survival of 8.1 months compared to five months for those who received placebo, with HR, 0.68 (95% CI, 0.49-0.94). Thus, median progression-free survival for all the women in the study (those with and without HRD) was improved with PARPi: 14 months vs. eight months for those who received placebo, with HR, 0.62 (95% CI, 0.50-0.76). However, even those patients with the worst prognoses were found to benefit from PARPi: Patients with only a partial response to chemotherapy who received PARPi had eight months of progression-free survival, compared to five months for those who received placebo. Similarly, in those patients whose initial treatment included neoadjuvant chemotherapy, those who received PARPi had 14 months of progression-free survival, whereas those who received placebo had only eight months of progression-free survival.
Side effects of niraparib include bone marrow suppression, low-grade nausea, and fatigue.
PARP inhibitors are revolutionizing ovarian cancer treatment. For some oncologists, these medications are familiar, since they are used upfront for the treatment of BRCA and HRD patients. PRIMA changes this scenario significantly, as it shows that all patients with advanced-stage, high-grade serous or endometrioid ovarian cancer may benefit from using a PARP inhibitor after finishing initial treatment with surgery and platinum-based chemotherapy, independent of BRCA or HRD. While BRCA germline testing remains important for cascade testing of family members, we no longer need to obtain BRCA germline testing right away during treatment, as PARPi now has been shown to be effective in all patients independent of BRCA status. In addition, we have been sending each patient’s ovarian cancer for molecular analysis, hoping they will have HRD, and thus qualify for initial treatment with PARPi. This molecular analysis is costly. The PRIMA study suggests that we can forgo molecular analysis and perhaps perform it later, when necessary, on fewer patients when seeking a new, targeted treatment option for subsequent recurrences. This likely will result in a substantial savings for our healthcare system.
In addition, the ovarian cancer patients whose initial remission lasts longer than six months are considered platinum-sensitive. We have been able to use PARPi in platinum-sensitive patients after their second-line treatment as long as they have had a response to second-line platinum therapy. These patients were already known to have the best prognosis of ovarian cancer patients, and it has been wonderful having this new tool to extend their second and subsequent remissions. However, it is the patients who are at highest risk of recurrence - those who are suboptimally tumor reduced or those who never had a complete response after initial treatment - for whom we are desperate for new treatments. PRIMA gives us a new tool to use for our most unfortunate patients, allowing even them to have a glimmer of hope for longer life.
Financial Disclosure: OB/GYN Clinical Alert’s Editor Jeffrey T. Jensen, MD, MPH, reports that he is a consultant for and receives grant/ research support from ObstetRx, Bayer, Merck, and Sebela; he receives grant/research support from AbbVie, Mithra, and Daré Bioscience; and he is a consultant for CooperSurgical and the Population Council. Peer Reviewer Catherine Leclair, MD; Nurse Planner Marci Messerle Forbes, RN, FNP; Editorial Group Manager Leslie Coplin; Editor Jason Schneider; and Executive Editor Shelly Mark report no financial relationships relevant to this field of study.