LYNPARZA® (olaparib) in Combination With Abiraterone Significantly Delayed Disease Progression in Patients Regardless of Biomarker Status in PROpel Phase 3 Trial in First-Line Metastatic Castration-Resistant Prostate Cancer (mCRPC)
September 24, 2021 at 06:45 AM EDT
AstraZeneca and Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced positive results from the Phase 3 PROpel trial, in which LYNPARZA in combination with abiraterone and prednisone demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of radiographic progression-free survival (rPFS) versus abiraterone plus prednisone as a first-line treatment for men with metastatic castration-resistant prostate cancer (mCRPC) with or without homologous recombination repair (HRR) gene mutations.
At a planned interim analysis, the Independent Data Monitoring Committee concluded that the trial met the primary endpoint of rPFS in men with mCRPC who had not received treatment in the first-line setting, including new hormonal agents (NHAs) or chemotherapy. The trial also showed a trend at this interim analysis towards improved overall survival (OS). However, the OS data are still immature, and the trial will continue to assess OS as a key secondary endpoint. The safety and tolerability were consistent with the known profiles of each medicine and will continue to be assessed.
Globally, prostate cancer is the second most common cancer in men, with an estimated 1.4 million patients diagnosed worldwide in 2020. Approximately 10-20% of men with advanced prostate cancer are estimated to develop CRPC within five years, and at least 84% of these men may develop metastases at the time of CRPC diagnosis.
Susan Galbraith, executive vice president, oncology R&D, AstraZeneca, said, “Today, men with metastatic castration-resistant prostate cancer have limited options in the first-line setting, and sadly often the disease progresses after initial treatment with current standards of care. These exciting results demonstrate the potential for LYNPARZA with abiraterone to become a new first-line option for these patients regardless of their biomarker status and may help reach a broad population of patients living with this aggressive disease. We look forward to discussing the results with global health authorities as soon as possible.”
Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, “We are encouraged by the PROpel results and the clinical benefit LYNPARZA in combination with abiraterone demonstrated versus abiraterone as a potential first-line treatment option for men with metastatic castration-resistant prostate cancer. These data build on Merck and AstraZeneca’s commitment to bring LYNPARZA to earlier lines of treatment and to more patients with advanced prostate cancer.”
The data will be presented at an upcoming medical meeting.
The trial enrolled men with or without HRR gene mutations. They may have previously been treated with docetaxel at a prior stage of disease. The trial excluded men with prior treatment with abiraterone. Treatment with any other NHA must have been stopped one year or longer prior to randomization. Men must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 and be a candidate for abiraterone treatment with documented evidence of progressive disease.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.
If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.
Pneumonitis: Occurred in 0.8% of patients exposed to LYNPARZA monotherapy, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.
Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.
Venous Thromboembolic Events: Including pulmonary embolism, occurred in 7% of patients with metastatic castration-resistant prostate cancer who received LYNPARZA plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. Patients receiving LYNPARZA and ADT had a 6% incidence of pulmonary embolism compared to 0.8% of patients treated with ADT plus either enzalutamide or abiraterone. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism, and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated.
ADVERSE REACTIONS—First-Line Maintenance BRCAm Advanced Ovarian Cancer
Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: decrease in hemoglobin (87%), increase in mean corpuscular volume (87%), decrease in leukocytes (70%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease in platelets (35%), and increase in serum creatinine (34%).
ADVERSE REACTIONS—First-Line Maintenance Advanced Ovarian Cancer in Combination with Bevacizumab
In addition, venous thromboembolic events occurred more commonly in patients receiving LYNPARZA/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients for LYNPARZA in combination with bevacizumab in the first-line maintenance setting for PAOLA-1 were: decrease in hemoglobin (79%), decrease in lymphocytes (63%), increase in serum creatinine (61%), decrease in leukocytes (59%), decrease in absolute neutrophil count (35%) and decrease in platelets (35%).
ADVERSE REACTIONS—Maintenance Recurrent Ovarian Cancer
Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), decreased appetite (21%) and dyspepsia (20%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).
ADVERSE REACTIONS—Advanced gBRCAm Ovarian Cancer
Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), mean corpuscular volume elevation (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).
ADVERSE REACTIONS—gBRCAm, HER2-Negative Metastatic Breast Cancer
Most common laboratory abnormalities (Grades 1-4) in >25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).
ADVERSE REACTIONS—First-Line Maintenance gBRCAm Metastatic Pancreatic Adenocarcinoma
Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for POLO were: increase in serum creatinine (99%), decrease in hemoglobin (86%), increase in mean corpuscular volume (71%), decrease in lymphocytes (61%), decrease in platelets (56%), decrease in leukocytes (50%), and decrease in absolute neutrophil count (25%).
ADVERSE REACTIONS—HRR Gene-mutated Metastatic Castration Resistant Prostate Cancer
Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for PROfound were: decrease in hemoglobin (98%), decrease in lymphocytes (62%), decrease in leukocytes (53%), and decrease in absolute neutrophil count (34%).
CYP3A Inhibitors: Avoid coadministration of strong or moderate CYP3A inhibitors when using LYNPARZA. If a strong or moderate CYP3A inhibitor must be coadministered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.
CYP3A Inducers: Avoid coadministration of strong or moderate CYP3A inducers when using LYNPARZA.
USE IN SPECIFIC POPULATIONS
Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.
Hepatic Impairment: No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C).
Renal Impairment: No dosage modification is recommended in patients with mild renal impairment (CLcr 51-80 mL/min estimated by Cockcroft-Gault). In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the dose of LYNPARZA to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).
INDICATIONS for LYNPARZA in the United States
First-Line Maintenance BRCAm Advanced Ovarian Cancer
First-Line Maintenance HRD-Positive Advanced Ovarian Cancer in Combination with Bevacizumab
Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
Maintenance Recurrent Ovarian Cancer
Advanced gBRCAm Ovarian Cancer
gBRCAm HER2-Negative Metastatic Breast Cancer
First-Line Maintenance gBRCAm Metastatic Pancreatic Cancer
HRR Gene-mutated Metastatic Castration Resistant Prostate Cancer
Please click here for complete Prescribing Information, including Patient Information (Medication Guide).
About LYNPARZA® (olaparib)
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
About the AstraZeneca and Merck Strategic Oncology Collaboration
Merck’s Focus on Cancer
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