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QUADRA Trial Implications
My Thoughts on the Clinical Implications of the Expanded Indication for Niraparib

Released: November 26, 2019

Expiration: November 24, 2020

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In this commentary, I discuss the phase II QUADRA trial that led to the recent FDA expanded approval of the PARP inhibitor niraparib in patients with ovarian cancer, specifically heavily pretreated patients with ≥ 3 previous lines of chemotherapy whose cancer is homologous recombination deficiency (HRD) positive as detected by a companion diagnostic test. HRD is defined by the presence of a BRCA mutation or genomic instability in patients who are platinum sensitive. It is the first indication of a PARP inhibitor in ovarian cancer that requires a companion diagnostic HRD test.

Background and QUADRA Study Design
The QUADRA study is very unique in that it really is the first and the largest study of its kind to prospectively study women with recurrent ovarian cancer who received multiple lines of chemotherapy. Traditionally, oncology clinical trials often limit the number of previous lines of chemotherapy in order to enroll a more homogenous patient population to evaluate the efficacy of new drugs. The QUADRA study reflects an understanding of what is happening right now in ovarian cancer: Despite no changes in incidence of ovarian cancer and mortality from the disease, currently we have a higher prevalence in both the United States and Europe of ovarian cancer than at any point in history. This is probably due to better supportive care, better use of agents at our disposal, and increasing use of maintenance therapy as well as other active therapies in the platinum-sensitive setting that incrementally improve both PFS and OS. Although we certainly are still striving to cure women with ovarian cancer, the fact that we are in an era when patients are living longer is exciting. That translates into what we see in the clinic, which is more and more patients are presenting with 5-7 previous lines of chemotherapy who still have good quality of life with good performance status and want more treatment. Before QUADRA, we just did not have prospective data to inform how to treat a patient who has received that many previous lines of chemotherapy.

The QUADRA study sought to evaluate the efficacy of the PARP inhibitor niraparib in later lines of therapy across biomarker subgroups including BRCA-mutated and other HRD-positive ovarian cancer. There were amendments made to the study to limit the enrollment to fourth-line and fifth-line patients, and the primary endpoint was ORR in HRD-positive, platinum-sensitive patients who received 3-4 previous lines of chemotherapy but no prior PARP inhibitor. Overall, more than 450 patients were enrolled with a variety of previous treatment histories, which provided a wealth of information.

Key Findings From the QUADRA Study
The most important findings from QUADRA was that the primary endpoint of ORR in HRD-positive, platinum-sensitive patients who received 3-4 previous lines of chemotherapy was 28% with a median duration of more than 9 months, which was pretty remarkable. In patients who had a BRCA mutation, the ORR was even higher at 39%. In comparison, the expected ORR in this setting is < 10% based on retrospective historical data.

An additional subset of patients achieved stable disease, which is also a clinical benefit that can be meaningful over many months until the next line of therapy. Stable disease is important and relevant from a clinical standpoint when you are making decisions for your patients, especially in later lines of therapy. In the QUADRA study, almost 60% of the BRCA-mutated, platinum-sensitive patients achieved clinical benefit at 24 weeks. In platinum-sensitive patients who were HRD positive without a BRCA mutation, the clinical benefit rate at 24 weeks was 40%. So these are important, real-world endpoints that clinicians need to know about when they are thinking of their patients because clinical benefit at 6 months or more is meaningful to patients.

The last clinically relevant endpoint from QUADRA was OS with the median approximately 17 months from enrollment compared with historical benchmarks of 5-9 months. Certainly, the QUADRA population is a select group of patients who were fit enough to go on a clinical trial and tolerate an oral regimen, although the eligibility criteria were very broad. Nevertheless, the median OS almost doubled when compared with historical data, which again gives us an indication of what we are seeing now with these newer benchmarks: that patients are living longer and doing better with exposure to an active agent.

Clinical Implications
From both a regulatory standpoint and a real-world clinician perspective, niraparib provides an active, tolerable, oral regimen that clearly has efficacy in heavily pretreated patients with ovarian cancer who are HRD positive, and it really should be thought of in patients who meet the criteria. It is true that the earlier you use a PARP inhibitor, the better the outcomes are. However, we have hundreds of thousands of patients living with ovarian cancer right now who have received 3 or more lines of previous chemotherapy regimens but not a PARP inhibitor, and niraparib gives them access to a very active agent with certain expectations for clinical benefit. This patient population will continue to exist for the next several years, and this is the reason for the label expansion of niraparib that will allow us to not leave any patient behind in terms of having access to a PARP inhibitor. I think that is incredibly important and it is an exciting advance for our patients with ovarian cancer.

HRD Testing in Ovarian Cancer
Given the recent label expansion of niraparib, I think for patients in later lines of therapy who have not had the opportunity to access a PARP inhibitor, HRD testing becomes urgent if it has not been done before. We want to find out which of our patients are HRD positive so that we can determine if they are eligible for niraparib. There is a companion diagnostic test that is required for prescribing niraparib in this setting, and I expect that the rate of HRD testing will likely increase for that reason alone.

Currently, many clinicians are not testing for HRD because it has not necessarily been required for prescribing PARP inhibitors for their patients. Whether or not HRD testing becomes a required companion diagnostic for additional expected future indications of PARP inhibitors will depend on the actual labels. The data from multiple phase III studies of PARP inhibitors as first-line maintenance therapy in ovarian cancer that were presented at ESMO 2019 were positive regardless of HRD status, so HRD may or may not be a required companion diagnostic test if and when they are approved by the FDA in this disease setting. If the labels do not require HRD testing, clinicians may still use an HRD assay to help fine-tune to whom they might give a PARP inhibitor and for whom they might use bevacizumab.

Your Thoughts
What are your questions and thoughts on the QUADRA trial and the label expansion of niraparib in ovarian cancer? I encourage you to answer the polling question and share your thoughts in the discussion box below.