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Lynparza (olaparib) Approved by FDA as First-Line Maintenance Treatment with Bevacizumab for HRD-Positive Advanced Ovarian Cancer

KENILWORTH, N.J.--(BUSINESS WIRE)--May 8, 2020 -- AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved Lynparza in combination with bevacizumab as a first-line maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability. Patients will be selected for therapy based on an FDA-approved companion diagnostic for Lynparza.

The approval was based on a biomarker subgroup analysis of 387 patients with HRD-positive tumors from the Phase 3 PAOLA-1 trial, which showed that Lynparza in combination with bevacizumab reduced the risk of disease progression or death by 67% (HR 0.33 [95% CI, 0.25-0.45]). It improved progression-free survival (PFS) to a median of 37.2 months vs. 17.7 months with bevacizumab alone in patients with HRD-positive advanced ovarian cancer.

The most common adverse reactions (ARs) ≥10% in the overall trial population for PAOLA-1 when treated with Lynparza in combination with bevacizumab (N=535) and at a ≥5% frequency compared to bevacizumab alone (N=267) were fatigue (53% vs. 32%), nausea (53% vs. 22%), anemia (41% vs. 10%), lymphopenia (24% vs. 9%), vomiting (22% vs. 11%) and leukopenia (18% vs. 10%). Grade 3 or above ARs were anemia (17% vs. <1%), lymphopenia (7% vs. 1%), fatigue (5% vs. 2%), nausea (2% vs. 1%), leukopenia (2% vs. 2%) and vomiting (2% vs. 2%). Additional adverse reactions that occurred in ≥10% of patients receiving Lynparza in combination with bevacizumab irrespective of the frequency compared to bevacizumab alone were diarrhea (18%), neutropenia (18%), urinary tract infection (15%) and headache (14%). Fatal adverse reactions occurred in one patient due to concurrent pneumonia and aplastic anemia. Serious adverse reactions occurred in 31% of patients who received Lynparza in combination with bevacizumab. Serious adverse reactions in >5% of patients included hypertension (19%) and anemia (17%).

In addition, venous thromboembolic events occurred more commonly in patients receiving Lynparza in combination with bevacizumab (5%) than in those receiving bevacizumab alone (1.9%). ARs led to dose interruption in 54% of patients on Lynparza in combination with bevacizumab, while 41% of patients on Lynparza in combination with bevacizumab had a dose reduction. Discontinuation of treatment due to ARs occurred in 20% of patients on Lynparza in combination with bevacizumab.

Approximately one in two women with advanced ovarian cancer has an HRD-positive tumor. For patients with advanced ovarian cancer, the primary aim of first-line maintenance treatment is to delay disease progression for as long as possible.

Isabelle Ray-Coquard, principal investigator of the PAOLA-1 trial and medical oncologist, Centre Léon Bérard and President of the GINECO group, said, “Ovarian cancer is a devastating disease. The magnitude of benefit in HRD-positive patients in the PAOLA-1 trial is impactful. I look forward to seeing this translate into clinical practice.”

Dave Frederickson, executive vice president, head of the oncology business unit, AstraZeneca, said, “This approval represents another milestone for Lynparza in patients with ovarian cancer. The median progression-free survival of more than three years offers new hope for women to delay relapse in this difficult-to-treat disease. These results further establish that HRD-positive is a distinct subset of ovarian cancer and HRD testing is now a critical component of diagnosis and tailoring of treatment for women with advanced ovarian cancer.”

Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, “Advances in understanding the role of biomarkers and PARP inhibition have fundamentally changed how physicians treat this aggressive type of cancer. Today’s approval based on the PAOLA-1 trial highlights the importance of HRD testing at diagnosis to identify those who may benefit from Lynparza in combination with bevacizumab as a first-line maintenance treatment.”

The full results from the Phase 3 PAOLA-1 trial were published in The New England Journal of Medicine.

Regulatory reviews are currently underway in the European Union, Japan and other countries for Lynparza in combination with bevacizumab as a first-line maintenance treatment for patients with advanced ovarian cancer. As part of a broad development program, Lynparza is being assessed as a monotherapy and in combination across multiple tumor types.

INDICATIONS

Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

First-Line Maintenance BRCAm Advanced Ovarian Cancer

For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza.

First-Line Maintenance HRD Positive Advanced Ovarian Cancer in Combination with Bevacizumab

In combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either:

a deleterious or suspected deleterious BRCA mutation and/or
genomic instability
Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza.

Maintenance Recurrent Ovarian Cancer

For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

Advanced gBRCAm Ovarian Cancer

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza.

gBRCAm HER2-Negative Metastatic Breast Cancer

For the treatment of adult patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza.

First-Line Maintenance gBRCAm Metastatic Pancreatic Cancer

For the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza.

About PAOLA-1

PAOLA-1 is a double-blind Phase 3 trial evaluating the efficacy and safety of Lynparza in combination with standard-of-care bevacizumab vs. bevacizumab alone, as a first-line maintenance treatment for advanced FIGO Stage III-IV high grade serous or endometroid ovarian, fallopian tube, or peritoneal cancer patients who had a complete or partial response to first-line treatment with platinum-based chemotherapy and bevacizumab.

PAOLA-1 is an ENGOT (European Network of Gynaecological Oncological Trial groups) trial, sponsored by ARCAGY Research (Association de Recherche sur les CAncers dont GYnécologiques) on behalf of GINECO (Groupe d’Investigateurs National des Etudes des Cancers Ovariens et du sein). ARCAGY-GINECO is an academic group specializing in clinical and translational research in patients’ cancers and a member of the GCIG (Gynecologic Cancer InterGroup).

In the U.S., eligible advanced ovarian cancer patients will be selected for therapy based on the FDA-approved myChoice HRD Plus, an HRD test designed to detect when a tumor has lost the ability to repair double-stranded DNA breaks. Myriad Genetics, Inc. owns and commercializes myChoice HRD Plus.

About Lynparza (olaparib)

Lynparza is a first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of tumor types with defects and dependencies in the DDR.

Lynparza, which is being jointly developed and commercialized by AstraZeneca and Merck, has a broad and advanced clinical trial development program, and AstraZeneca and Merck are working together to understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types.

About Ovarian Cancer

Ovarian cancer is the fifth most common cause of death from cancer in women in the United States. This year, it is estimated that more than 21,000 women will be diagnosed with ovarian cancer and nearly 14,000 women will die of this disease.

Women with ovarian cancer are often diagnosed with advanced disease, which has a five-year survival rate of about 48%. For newly diagnosed advanced ovarian cancer, the primary aim of treatment is to delay progression of the disease for as long as possible. BRCA1/2 mutations are found in approximately 22% of all ovarian cancers and approximately 50% of ovarian cancers are HRD-positive.

About Homologous Recombination Deficiency

HRD encompass a wide range of genetic abnormalities, including BRCA mutations, that can be detected using tests. As the BRCA gene drives DNA repair via homologous recombination, mutation of this gene leads to homologous recombination deficiency thereby interfering with normal cell DNA repair mechanisms. BRCA mutations are just one of many HRDs which confer sensitivity to PARP inhibitors including LYNPARZA.

About the AstraZeneca and Merck Strategic Oncology Collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialize certain oncology products, including LYNPARZA, the world’s first PARP inhibitor, for multiple cancer types. Working together, the companies will develop these products in combination with other potential new medicines and as monotherapies. Independently, the companies will develop these oncology products in combination with their respective PD-L1 and PD-1 medicines.

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

About Merck

For more than 125 years, Merck, known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases in pursuit of our mission to save and improve lives. We demonstrate our commitment to patients and population health by increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to prevent and treat diseases that threaten people and animals – including cancer, infectious diseases such as HIV and Ebola, and emerging animal diseases – as we aspire to be the premier research-intensive biopharmaceutical company in the world. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA

This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of the recent global outbreak of novel coronavirus disease (COVID-19); the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s 2019 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Source: Merck & Co., Inc.

Posted: May 2020

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