Merck and AstraZeneca’s LYNPARZA Reduced the Risk of Disease Progression or Death by 51% in Men with Homologous Recombination Repair (HRR) Gene Mutations
First Positive Phase 3 Trial Evaluating a Targeted Treatment in Biomarker-Selected Prostate Cancer Patients
KENILWORTH, NJ, USA I September 30, 2019 I AstraZeneca and Merck (NYSE:MRK), known as MSD outside the United States and Canada, today presented detailed results from the Phase 3 PROfound trial in 387 men with metastatic castration-resistant prostate cancer (mCRPC) who have a mutation in their homologous recombination repair (HRR) genes and whose disease had progressed on prior treatment with new hormonal agent (NHA) treatments e.g. abiraterone or enzalutamide.
The trial was designed to analyze men with mCRPC harboring HRR-mutated (HRRm) genes in two cohorts: the primary endpoint was in those with mutations in BRCA1/2 or ATM genes and then, if LYNPARZA showed clinical benefit, a formal analysis was performed of the overall trial population of men with HRRm genes (BRCA1/2, ATM, CDK12 and 11 other HRRm genes).
Results showed a statistically-significant and clinically-meaningful improvement with LYNPARZA in the primary endpoint of radiographic progression-free survival (rPFS) in BRCA1/2 or ATM-mutated tumors reducing the risk of disease progression or death by a median of 7.4 months versus 3.6 months for those receiving abiraterone or enzalutamide (HR 0.34 [95% CI, 0.25-0.47], p<0.0001). LYNPARZA reduced the risk of disease progression or death by 66% for these men.
The trial also met the key secondary endpoint of rPFS in the overall HRRm population, where LYNPARZA reduced the risk of disease progression or death by 51% and improved rPFS to a median of 5.8 months vs. 3.5 months for those receiving abiraterone or enzalutamide (HR 0.49 [95% CI, 0.38-0.63], p<0.0001).
Results were presented during the Presidential Symposium at the 2019 European Society of Medical Oncology (ESMO) congress in Barcelona, Spain (LBA #12).
Dr. José Baselga, executive vice president, oncology R&D, AstraZeneca, said, “Results from PROfound demonstrate that, in addition to providing substantial benefit as a precision medicine for men with metastatic castration-resistant prostate cancer with BRCA-mutated tumors, LYNPARZA is effective beyond just BRCA in tumors with mutations in other genes associated with homologous recombination repair. PROfound validates the concept of PARP sensitivity across multiple genes associated with homologous recombination repair in this disease and marks the first positive Phase 3 trial using a molecular biomarker to identify men for targeted treatment for metastatic castration-resistant prostate cancer. We are working with global health 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, “The results from the Phase 3 PROfound trial are a testament to Merck and AstraZeneca’s lasting commitment to patients with cancer. The trial met the primary endpoint in men with metastatic castration-resistant prostate cancer that progressed on prior hormonal therapy, a notoriously difficult-to-treat disease. The benefit seen in patients beyond just those with BRCA mutations underscores the potential value of genomic testing in prostate cancer.”
Maha Hussain, one of the principal investigators of the PROfound trial and deputy director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, said, “We have seen advances in the treatment over the last 15 years for men with metastatic castration-resistant prostate cancer. However, to date treatments for this state of disease continue to use ‘one size fits all’ approaches overlooking the genomic make-up of the tumor and how it could inform treatment decisions to better personalize care and impact outcomes. I am thrilled by the PROfound results and LYNPARZA’s clinically meaningful benefit, which offers the potential of a molecularly targeted treatment for this patient population with advanced disease. I am confident we are now entering a new era of personalized care and precision medicine for metastatic castration-resistant prostate cancer.”
In the key secondary endpoint of time to pain progression (TTPP), median TTPP was not reached with LYNPARZA and was 9.92 months with abiraterone and enzalutamide in patients with BRCA1/2 or ATM mutations (HR 0.44 [95% CI, 0.22-0.91], p 0.0192).
Results also showed a trend at this interim analysis time point for improvement in overall survival (OS), another key secondary endpoint. LYNPARZA extended OS to a median of 18.5 months versus 15.1 months for abiraterone or enzalutamide in men with BRCA1/2 or ATM-mutated tumors (HR 0.64 [95% CI, 0.43-0.97], p<0.0173), of which 81% started on abiraterone or enzalutamide and, following confirmed disease progression, then switched to LYNPARZA. At this interim analysis, the OS endpoint did not meet statistical significance. In an exploratory analysis, a similar trend in OS was observed at this interim analysis in the HRRm population with a median of 17.5 months for men treated with LYNPARZA vs. 14.3 months for those receiving abiraterone or enzalutamide (HR 0.67 [95% CI, 0.49-0.93]).
The trial showed a confirmed overall response rate (ORR) a key secondary endpoint of 33.3% for LYNPARZA vs. 2.3% for abiraterone or enzalutamide in patients with BRCA1/2 or ATM mutations (p<0.0001). In an exploratory analysis of patients in the overall HRRm population, confirmed ORR was 21.7 % for LYNPARZA vs. 4.5% for patients receiving abiraterone or enzalutamide.
Summary of resultsi
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Cohort A ii (BRCA1/2 or ATM) |
Cohort A+B iii, v. (Overall HRRm) |
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Lynparza n=162 |
pcNHA n=83 |
Lynparza n=256 |
pcNHA n=131 |
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| rPFS | ||||
| Median, months | 7.4 | 3.6 | 5.8 | 3.5 |
| % progression-free at 6 months | 59.8 | 22.6 | 49.7 | 23.7 |
| % progression-free at 12 months | 28.1 | 9.4 | 22.1 | 13.5 |
| Hazard ratio (95% CI) | 0.34 (0.25-0.47) | 0.49 (0.38-0.63) | ||
| p-value | <0.0001 | <0.0001 | ||
| Confirmed ORR v. | ||||
| Patients with response (%) | 33.3 | 2.3 | 21.7 | 4.5 |
| Odds ratio (95% CI) | 20.86 (4.18-379.18) | 5.93 (2.01-25.40) | ||
| p-value | <0.0001 | 0.0006 (nominal)v. | ||
| Time to pain progression iiii | ||||
| Median, months | NR | 9.92 | ||
| Hazard ratio (95% CI) | 0.44 (0.22-0.91) | |||
| p-value | 0.0192 | |||
| OS (interim) iv, v. | ||||
| Median, months | 18.5 | 15.1 | 17.5 | 14.3 |
| Hazard ratio (95% CI) | 0.64 (0.43-0.97) | 0.67 (0.49-0.93) | ||
| p-value | 0.0173 | 0.0063 (nominal)v. | ||
| NR, not reached; ORR, objective response rate; pc, physician’s choice I Assessed by blinded independent central review (BICR) ii Cohort B included patients with any 1 of 12 other HRR mutations iii Time to pain progression in Cohort A was a secondary endpoint included in the formal testing hierarchy iv Interim analysis was done at 38% (Cohort A) and 41% (Cohort A+B) data maturity; Alpha spend at interim was 0.01; statistical significance not reached v. ORR and OS in Cohort A+B were exploratory analyses and not multiplicity controlled |
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The safety and tolerability profile of LYNPARZA in the PROfound trial was in line with that observed in prior clinical trials. The most common adverse events (AEs) ≥20% for LYNPARZA compared to abiraterone or enzalutamide were anemia (47% vs.15%), nausea (41% vs. 19%), fatigue and asthenia (41% vs. 32%), decreased appetite (30% vs. 18%), and diarrhea (21% vs. 7%). Grade 3 or above AEs were anemia (22% vs. 5%), fatigue and asthenia (3% vs. 5%), vomiting (2% vs. 1%), dyspnea (2% vs. 0%), urinary tract infection (2% vs. 4%), nausea (1% vs. 0%), decreased appetite (1% each), diarrhea (1% vs. 0%), and back pain (1% vs. 2%). AEs led to discontinuation of treatment in 16% of patients on LYNPARZA vs. 9% on abiraterone and enzalutamide.
AstraZeneca and Merck are also exploring additional trials in prostate cancer, including the ongoing Phase 3 PROpel trial, evaluating LYNPARZA as a first-line therapy in mCRPC for patients with or without HRR mutations, in combination with abiraterone acetate.
About PROfound
PROfound is a prospective, multi-center, randomized, open-label, Phase 3 trial evaluating the efficacy and safety of LYNPARZA versus enzalutamide or abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on prior treatment with a new hormonal anticancer treatment and have a qualifying tumor mutation in one of 15 genes involved in the homologous recombination repair (HRR) pathway, among them BRCA 1/2 , ATM and CDK12.
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 with gBRCAm advanced epithelial ovarian, fallopian tube or primary peritoneal cancer 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
In 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.
Please click here for complete Prescribing Information, including Patient Information (Medication Guide).
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 Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Prostate cancer is the second-most common cancer in men, with an estimated 1.6 million new cases diagnosed worldwide in 2015 and is associated with a significant mortality rate. Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone. mCRPC occurs when prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones. Approximately 10-20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these will have metastases at the time of CRPC diagnosis. Of men with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years. Despite an increase in the number of available therapies, five-year survival for men with mCRPC, remains low.
About Homologous Recombination Repair (HRR) Mutations
Homologous recombination repair (HRR) plays a significant role in maintaining the genetic stability of cells and suppressing tumor growth by repairing damaged DNA. Mutations, or defects, in homologous recombination (HR) pathway genes – which include ataxia telangiectasia mutated (ATM) and BRCA1/2 genes – increase the risk for breast, ovarian, pancreatic, prostate and other cancers.
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
