LYNPARZA® (olaparib) in Combination With Abiraterone and Prednisone or Prednisolone Receives Positive Opinion From EU CHMP as Treatment for Certain Patients With Metastatic Castration-Resistant Prostate Cancer
November 14, 2022 at 06:45 AM EST
First PARP inhibitor to demonstrate clinical benefit in radiographic progression-free survival in combination with a new hormonal agent with or without homologous recombination repair gene mutations
AstraZeneca and Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending approval of LYNPARZA in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated.
The CHMP based its positive opinion on results from the Phase 3 PROpel trial presented at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium and later published in NEJM Evidence.
These results showed LYNPARZA in combination with abiraterone and prednisone or prednisolone reduced the risk of disease progression or death by 34% (HR=0.66 [95% CI, 0.54-0.81]; p<0.0001) versus placebo plus abiraterone and prednisone or prednisolone. Median radiographic progression-free survival (rPFS) was 24.8 months for the LYNPARZA plus abiraterone arm versus 16.6 months for the placebo plus abiraterone arm, with or without homologous recombination repair (HRR) gene mutations.
The safety and tolerability of LYNPARZA in combination with abiraterone and prednisone or prednisolone was in line with that observed in prior clinical trials and the known profiles of the individual medicines. The most common adverse events (AEs) (≥20%) were anemia (46%), fatigue (37%) and nausea (28%). Grade ≥3 AEs were anemia (15%), hypertension (4%), urinary tract infection (2%), fatigue (2%), decreased appetite (1%), vomiting (1%), back pain (1%), diarrhea (1%) and nausea (0.3%). Approximately 14% of patients who received LYNPARZA in combination with abiraterone and prednisone or prednisolone discontinued treatment due to an AE.
Prostate cancer is the most commonly diagnosed cancer in men in Europe, with an estimated 473,000 cases and 108,000 deaths in 2020. Approximately 10-20% of patients with advanced prostate cancer are estimated to develop castration-resistant prostate cancer (CRPC) within five years, and at least 84% of these men will develop metastases at the time of CRPC diagnosis. Patients with advanced prostate cancer have a particularly poor prognosis, and the five-year survival rate remains low.
Noel Clarke, urological surgeon and professor of urological oncology at the Christie/Salford Royal Hospitals and University of Manchester and the PROpel trial joint senior investigator, said, “Patients with mCRPC in the European Union have limited treatment options. This form of advanced prostate cancer has a poor prognosis, and treatment decisions after initial diagnosis are critical. If approved in the European Union for prostate cancer of this type, olaparib in combination with abiraterone will provide a much-needed new treatment option for the many men with this condition.”
Susan Galbraith, executive vice president, oncology R&D, AstraZeneca, said, “With the incidence and mortality of prostate cancer set to double in the coming decades, it is more important than ever that we bring new treatment options to suitable patients at the earliest possible moment in their care. If approved, LYNPARZA in combination with abiraterone and prednisone or prednisolone will represent the first combination of a PARP inhibitor and a new hormonal agent available to patients in the European Union.”
Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories, said, “While prostate cancer has seen many advances in care in recent decades, for those with mCRPC, new treatment options are urgently needed. We are fully committed to bringing LYNPARZA in combination with abiraterone and prednisone or prednisolone to suitable patients in Europe as quickly as possible.”
LYNPARZA in combination with abiraterone and prednisone or prednisolone is undergoing priority review in the U.S. for the treatment of adult patients with mCRPC based on results from the Phase 3 PROpel trial, with a decision expected in Q4 2022.
LYNPARZA monotherapy is approved in the U.S. based on results from the Phase 3 PROfound trial for patients with HRR gene-mutated mCRPC (BRCA-mutated and other HRR gene mutations) who have progressed following prior treatment with enzalutamide or abiraterone; and in the European Union, Japan and China for patients with BRCA-mutated mCRPC who have progressed following prior therapy that included a new hormonal agent (NHA).
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 who received 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 who received 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—Adjuvant Treatment of gBRCAm, HER2-Negative, High-Risk Early Breast Cancer
Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the adjuvant setting for OlympiA were: decrease in lymphocytes (77%), increase in mean corpuscular volume (67%), decrease in hemoglobin (65%), decrease in leukocytes (64%), and decrease in absolute neutrophil count (39%).
ADVERSE REACTIONS—gBRCAm, HER2-Negative Metastatic Breast Cancer
Most common laboratory abnormalities (Grades 1-4) in >25% of patients who received LYNPARZA in the metastatic setting for 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 who received 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 who received 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
Adjuvant Treatment of gBRCAm, HER2-Negative, High-Risk Early Breast Cancer
gBRCAm HER2-Negative Metastatic Breast Cancer
First-Line Maintenance gBRCAm Metastatic Pancreatic Cancer
HRR Gene-mutated Metastatic Castration Resistant Prostate Cancer
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
Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA
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 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 Annual Report on Form 10-K for the year ended December 31, 2021 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).