On September 21, 2020 AstraZeneca and MSD’s Lynparza (olaparib) reported that has been recommended for marketing authorisation in the European Union (EU) for the 1st-line maintenance treatment with bevacizumab of patients with homologous recombination deficient (HRD)-positive advanced ovarian cancer (Press release, AstraZeneca, SEP 21, 2020, View Source [SID1234565401]).

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The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency based its positive opinion on a biomarker subgroup analysis of the PAOLA-1 Phase III trial, which was published in The New England Journal of Medicine.

The trial showed that Lynparza in combination with bevacizumab maintenance treatment reduced the risk of disease progression or death by 67% (based on a hazard ratio of 0.33; 95% confidence interval 0.25-0.45). The addition of Lynparza improved progression-free survival (PFS) to a median of 37.2 months versus 17.7 months with bevacizumab alone in patients with HRD-positive advanced ovarian cancer.

For patients with advanced ovarian cancer, the primary aim of 1st-line treatment is to delay disease progression for as long as possible with the intent to achieve long-term remission.1-3

Ovarian cancer is the fifth most common cause of cancer death in Europe and the five-year survival rate is approximately 45%, due in part because women are often diagnosed with advanced disease (Stage III or IV).4,5

José Baselga, Executive Vice President, Oncology R&D, said: "Half of all newly diagnosed patients with advanced ovarian cancer have HRD-positive tumours. Lynparza together with bevacizumab has demonstrated a median progression-free survival benefit of more than three years, offering new hope for women in this setting. This recommendation is a vital step toward addressing a significant unmet need and could bring a new treatment option that delays relapse in this devastating disease."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "HRD is an important biomarker of advanced ovarian cancer that can inform how physicians in the EU treat this aggressive type of cancer. This recommendation and the results from the PAOLA-1 trial underscore the importance of HRD testing at diagnosis to determine the best course of treatment for women with advanced ovarian cancer."

The CHMP recommendation is for Lynparza in combination with bevacizumab for the maintenance treatment of adult patients with advanced (FIGO stages III and IV) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of 1st-line platinum-based chemotherapy in combination with bevacizumab and whose cancer is associated with HRD positive status defined by either a breast cancer susceptibility gene 1/2 (BRCA1/2) mutation and/or genomic instability.

Further results from the PAOLA-1 trial recently presented during the 2020 European Society for Medical Oncology virtual congress showed that Lynparza in combination with bevacizumab maintenance treatment demonstrated a statistically significant improvement in the time to second disease progression (PFS2) versus bevacizumab alone in patients with HRD-positive advanced ovarian cancer, a key secondary endpoint. The results showed Lynparza with bevacizumab provided benefit beyond first disease progression, improving PFS2 to a median of 50.3 months versus 35.3 months with bevacizumab alone.

Lynparza in combination with bevacizumab is approved in the US and several other countries as a 1st-line maintenance treatment for patients with HRD-positive advanced ovarian cancer and is currently under regulatory review in other countries around the world.

Ovarian cancer

In 2018, there were nearly 68,000 new cases of ovarian cancer diagnosed in Europe and around 45,000 deaths.4 Approximately 50% of ovarian cancers are HRD-positive including BRCA1/2 mutation.6,7 Approximately 22% of ovarian cancers have a BRCA1/2 mutation.6-8

Homologous recombination deficiency

HRD, which defines a subgroup of ovarian cancer, encompasses a wide range of genetic abnormalities, including BRCA mutations and beyond. As with BRCA gene mutations, HRD interferes with normal cell DNA repair mechanisms and confers sensitivity to PARP inhibitors including Lynparza.9

PAOLA-1

PAOLA-1 is a double-blind Phase III trial testing the efficacy and safety of Lynparza added to standard-of-care bevacizumab versus bevacizumab alone, as a 1st-line maintenance treatment for newly diagnosed 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 1st-line treatment with platinum-based chemotherapy and bevacizumab. AstraZeneca and MSD announced in August 2019 that the trial met its primary endpoint of PFS in the overall trial population.

Lynparza

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2. 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 PARP-dependent tumour types with defects and dependencies in the DDR pathway.

Lynparza is currently approved in a number of countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer. It is approved in the US, the EU, Japan, China, and several other countries as 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in the US as a 1st-line maintenance treatment with bevacizumab for patients with HRD-positive advanced ovarian cancer (BRCAm and/or genomic instability). Lynparza is approved in the US, Japan, and a number of other countries for germline BRCA-mutated, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer. It is also approved in the US and several other countries for the treatment of germline BRCAm metastatic pancreatic cancer. Lynparza is approved in the US for HRR gene-mutated mCRPC (BRCAm and other HRR gene mutations). Regulatory reviews are underway in several countries for ovarian, breast, pancreatic and prostate cancers.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 30,000 patients worldwide. Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

The AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and Koselugo (selumetinib), a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.