AstraZeneca and Merck’s LYNPARZA Added to Bevacizumab Reduced the Risk of Disease Progression or Death by 41% in the Overall Trial Population of Women Who Responded to Platinum-Based Chemotherapy
KENILWORTH, NJ, USA I September 28, 2019 I AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced detailed positive results from the Phase 3 PAOLA-1 trial showing LYNPARZA added to bevacizumab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in women with newly-diagnosed advanced ovarian cancer who had a complete or partial response to first-line treatment with platinum-based chemotherapy and bevacizumab.
The trial compared LYNPARZA when added to standard-of-care (SoC) bevacizumab versus bevacizumab alone in women in the first-line maintenance setting, irrespective of their genetic biomarker status or outcome from previous surgery. Investigator-assessed results showed LYNPARZA added to bevacizumab reduced the risk of disease progression or death by 41% and improved PFS to a median of 22.1 months versus 16.6 months for those treated with bevacizumab alone (HR 0.59 [95% CI, 0.49-0.72], p<0.0001).
The sensitivity analysis of blinded independent central review (BICR) of PFS was consistent, showing a similar improvement with a median of 26.1 months for LYNPARZA added to bevacizumab versus 18.3 months for bevacizumab alone (HR 0.63 [95% CI, 0.51-0.77], p<0.0001).
The safety and tolerability profile of LYNPARZA and bevacizumab were consistent with those known from previous trials for each medicine.
The results were presented at the Presidential Symposium of the 2019 European Society of Medical Oncology (ESMO) congress in Barcelona, Spain (Abstract #LBA2_PR).
Dr. José Baselga, executive vice president, Oncology R&D, AstraZeneca, said, “This trial was designed to reflect everyday clinical practice and used a global standard-of-care treatment with LYNPARZA. We are working with regulatory authorities to bring LYNPARZA to these patients as quickly as possible.”
Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, “PAOLA-1 is the second positive Phase 3 trial involving LYNPARZA in the first-line maintenance setting for advanced ovarian cancer. Following the positive SOLO-1 trial, we are encouraged by the PAOLA-1 results which reaffirm AstraZeneca and Merck’s ongoing commitment to explore potential treatment options for more women with ovarian cancer.”
Isabelle Ray Coquard, principal investigator of the PAOLA-1 trial and medical oncologist, Department of Medical Oncology at the Clinical Science Institute of the Léon Bérard Centre and President of the GINECO (Groupe d’Investigateurs National des Etudes des Cancers Ovariens et du sein) group, said, “The goal of first-line, including maintenance treatment for women with newly-diagnosed advanced ovarian cancer, is to delay relapse. Unfortunately, the risk of relapse is high, as two out of three women relapse within three years of initial diagnosis. In PAOLA-1, the results of LYNPARZA added to bevacizumab were significant and have the potential to change clinical practice in how women with advanced ovarian cancer are treated in the first-line maintenance setting.”
The trial also included exploratory sub-group analyses including BRCA-mutated (BRCAm) and broader homologous recombination deficiency (HRD) populations. In the BRCAm-positive sub-group, LYNPARZA added to SoC bevacizumab vs. bevacizumab alone resulted in median PFS of 37.2 months versus 21.7 months (HR 0.31 [95% CI, 0.20-0.47]) and 18.9 months versus 16 months in the non-BRCAm sub-group (HR 0.71 [95% CI, 0.58-0.88]). For the HRD-positive sub-group, median PFS for LYNPARZA added to bevacizumab was 37.2 months versus 17.7 months with bevacizumab alone (HR 0.33 [95% CI, 0.25-0.45]). In the HRD-positive, non-BRCAm sub-group, there was a median PFS of 28.1 months with LYNPARZA added to bevacizumab versus 16.6 months on bevacizumab alone (HR 0.43 [95% CI, 0.28-0.66]). The HRD-negative/unknown sub-group results showed a median PFS of 16.9 months for LYNPARZA added to bevacizumab vs. 16 months for bevacizumab alone (HR 0.92 [95% CI, 0.72-1.17]).
Summary of PFS in overall population:
| Median in months | Hazard Ratio (95% CI) | ||
| LYNPARZA + bevacizumab |
bevacizumab alone |
||
|
PFS (investigator assessed) (n=806) |
22.1 | 16.6 |
0.59 (0.49-0.72) p<0.0001 |
| PFS (BICR) | 26.1 | 18.3 |
0.63 (0.51-0.77) p<0.0001 |
Summary of PFS in exploratory subgroup analyses:
| Median in months | Hazard Ratio (95% CI) | ||
| LYNPARZA + bevacizumab |
bevacizumab alone |
||
| PFS by BRCAm status | |||
| BRCAm (n=237) | 37.2i. | 21.7 | 0.31 (0.20-0.47) |
| Non-BRCAm (n=569) | 18.9 | 16.0 | 0.71 (0.58-0.88) |
| PFS by HRD status | |||
| HRD-positive (n=387) | 37.2i. | 17.7 | 0.33 (0.25-0.45) |
| HRD-positive, non-BRCAm (n=152) | 28.1i. | 16.6 | 0.43 (0.28-0.66) |
| HRD-negative/unknown (n=419) | 16.9 | 16.0 | 0.92 (0.72-1.17) |
| i The median PFS estimate is immature at this time (below 50% maturity) and will evolve with additional follow up | |||
The most common adverse events (AEs) ≥20% for LYNPARZA plus bevacizumab compared to bevacizumab alone were nausea (53% vs. 22%), fatigue (53% vs. 32%), hypertension (46% vs. 60%), anemia (41% vs. 10%), lymphopenia (24% vs. 10%), vomiting (22% vs. 11%) and arthralgia (22% vs. 24%). Overall Grade 3 or above (AEs) were 57% for LYNPARZA added to bevacizumab and 51% for bevacizumab alone. Grade 3 or above AEs were hypertension (19% vs. 30%), anemia (17% vs. 0.4%), lymphopenia (7% vs. 1%), fatigue (5% vs. 2%), neutropenia (6% vs 3%), nausea (2% vs. 1%), diarrhea (2% each), leukopenia (2% vs. 1%), vomiting (2% each) and abdominal pain (1% vs. 2% AEs led to dose interruption in 54% of patients on LYNPARZA plus bevacizumab vs. 24% on bevacizumab alone, while 20% of patients on LYNPARZA plus bevacizumab discontinued treatment vs. 6% on bevacizumab alone.
LYNPARZA, which is being jointly developed and commercialized by Merck and AstraZeneca, is currently approved in 64 countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer regardless of BRCA status. It is approved in the U.S. as first-line maintenance treatment in BRCAm advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in 38 countries, including the U.S., countries in the EU, and Japan, for germline BRCAm HER2-negative metastatic breast cancer previously treated with chemotherapy; in the EU this includes locally advanced breast cancer. LYNPARZA has been used to treat over 25,000 patients worldwide.
LYNPARZA is the only PARP inhibitor with positive Phase 3 trials in four different cancer types.
About PAOLA-1
PAOLA-1 is a double-blind Phase 3 trial evaluating the efficacy and safety of LYNPARZA added to SoC bevacizumab vs. bevacizumab alone, as a first-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 first-line treatment with platinum-based chemotherapy and bevacizumab. The intent-to-treat* population refers to all patients randomized in the trial.
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 specialising in clinical and translational research in patients’ cancers and a member of the GCIG (Gynecologic Cancer InterGroup).
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 the eighth most common cause of death from cancer in women worldwide, with a five-year survival rate of approximately 19%. In 2018, there were nearly 300,000 new cases diagnosed and around 185,000 deaths.
About Homologous Recombination Deficiency (HRD)
Homologous recombination deficiencies (HRDs), including BRCA, cause genomic instability which can be detected using assays such as the Myriad My Choice HRD test. BRCA mutations are just one of many homologous recombination repair deficiencies which are found in up to half of newly diagnosed advanced ovarian cancer patients.
About GINECO
GINECO (Groupe d’Investigateurs Nationaux pour l’Étude des Cancers Ovariens et du sein) is the French Cooperative Group in Oncology labelled by INCA (Institut National du Cancer or French NCI) developing and conducting gynaecological and metastatic breast cancer clinical trials at the national and international level. Founded in 1993, the GINECO group is member of international consortia such as ENGOT and GCIG.
About ENGOT
ENGOT (European Network for Gynaecological Oncological Trial groups) is a research network of the European Society of Gynaecological Oncology (ESGO). Founded in 2007, ENGOT includes 21 cooperative groups from 25 European countries.
About GCIG
The GCIG (Gynecological Cancer InterGroup) aims to promote and facilitate high quality clinical trials in order to improve outcomes for women with gynaecological cancer. Founded in 1998, GCIG includes 23 cooperative groups from 28 countries worldwide.
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 LYNPARZA, the world’s first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. Working together, the companies will develop LYNPARZA and selumetinib in combination with other potential new medicines and as monotherapies. Independently, the companies will develop LYNPARZA and selumetinib 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 a century, Merck, a leading global biopharmaceutical company 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. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world – including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease and infectious diseases including HIV and Ebola. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
SOURCE: Merck
