LYNPARZA® (olaparib) in Combination with Abiraterone Delayed Disease Progression in Metastatic Castration-Resistant Prostate Cancer

KENILWORTH, N.J.--(BUSINESS WIRE)-- AstraZeneca and Merck (NYSE:MRK), known as MSD outside the United States and Canada, today presented data which showed clinical improvement in median radiologic progression-free survival (rPFS) with LYNPARZA^® (olaparib) in combination with abiraterone compared to abiraterone monotherapy, a current standard of care, in metastatic castration-resistant prostate cancer (mCRPC). LYNPARZA is being jointly developed and commercialized by AstraZeneca and Merck.

The results of Study 08, a randomized, double-blinded, multi-center Phase 2 trial, comparing LYNPARZA in combination with abiraterone (n=71) to abiraterone monotherapy (n=71) in patients with previously-treated mCRPC, regardless of homologous recombination repair (HRR) mutation status, were presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting as a “Best of ASCO presentation” and were published online today in The Lancet Oncology. The primary endpoint was rPFS. Secondary endpoints included time to second progression or death (PFS2), overall survival (OS) and health-related quality of life.

LYNPARZA is not FDA-approved for prostate cancer. LYNPARZA is indicated for the treatment of advanced ovarian cancer patients with a gBRCA mutation previously treated with three or more lines of chemotherapy; for the maintenance treatment of recurrent ovarian cancer in response to platinum-based chemotherapy regardless of BRCA mutation status; and for the treatment of gBRCA HER2-negative metastatic breast cancer after chemotherapy and prior endocrine therapy, if appropriate. Physicians should select advanced ovarian cancer and metastatic breast cancer patients for therapy based on a FDA-approved companion diagnostic. Please see Indications for LYNPARZA^® (olaparib) 100 mg in the U.S. below.

Noel Clarke, professor of urological oncology, Christie NHS Foundation Trust, Manchester, United Kingdom, said, “This is the first time we have seen an improvement with the use of a PARP inhibitor in combination with abiraterone in patients with metastatic castration-resistant prostate cancer, and this effect may be independent of HRR status. The data suggest this therapeutic combination may be a promising new treatment approach for this aggressive disease.”

Sean Bohen, executive vice president, global medicines development and chief medical officer at AstraZeneca, said, “A previous trial demonstrated improvements in response rates with LYNPARZA monotherapy in metastatic castration-resistant patients with HRR mutations. The Study 08 combination data suggest that, regardless of their mutation status, men with metastatic castration-resistant prostate cancer may potentially benefit from LYNPARZA in combination with abiraterone.”

Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, “There is a significant unmet medical need for patients with metastatic castration-resistant prostate cancer as they are a high-risk group with limited treatment options. LYNPARZA is the first PARP inhibitor to demonstrate activity in combination with standard-of-care treatment in prostate cancer. These data from Study 08 represent another important milestone in the clinical development of LYNPARZA.”

Median rPFS was 13.8 months with LYNPARZA and abiraterone compared to 8.2 months with abiraterone alone (HR=0.65 [95% CI, 0.44-0.97]; p=0.034). Median PFS2 was 23.3 months versus 18.5 months (HR=0.79 [95% CI, 0.51-1.21]). Median OS was 22.7 months with combination treatment versus 20.9 months with abiraterone alone (HR=0.91; [95% CI, 0.60-1.38]). Pre-specified exploratory subgroup analyses demonstrated an rPFS improvement in patients regardless of HRR status (see Table 1). Study 08 was not powered for subgroup analyses, PFS2 and OS. HRR mutation status was not known for all patients.

Table 1: rPFS by HRR status
						Median rPFS (months)										HR					95% CI
						LYNPARZA + abiraterone					abiraterone
Overall (n=142)						13.8					8.2					0.65					0.44-0.97
HRR-mutation (n=21)						17.8					6.5					0.74					0.26-2.12
Wild-type HRR (n=35)						15.0					9.7					0.52					0.24-1.15
Partially-characterized HRR status (n=86)*						13.1					6.4					0.67					0.40-1.13

*Those whose plasma and blood samples both tested negative for HRR mutations, but for whom no valid tumor test result was available

The safety of LYNPARZA in combination with abiraterone was also reported, as was the safety of abiraterone monotherapy. Grade ≥3 adverse events (AEs), serious AEs and treatment discontinuations due to AEs were more frequent with combination treatment than abiraterone alone (54% vs 28%; 34% vs 18%; 30% vs 10%, respectively). The most common grade ≥3 AEs in the combination arm were anemia (21%), pneumonia (6%) and myocardial infarction (6%). Serious cardiovascular events occurred in seven patients in the combination group and one patient in the abiraterone group. LYNPARZA is associated with a number of serious, potentially fatal risks, including MDS-AML, pneumonitis and embryo-fetal toxicity. Please see Important Safety Information for LYNPARZA^® (olaparib) tablets 100 mg below.

In addition to Study 08, other studies are underway to explore the potential of LYNPARZA as a monotherapy for HRR-mutated mCRPC, including PROfound, which is testing LYNPARZA monotherapy versus enzalutamide or abiraterone in patients with previously-untreated mCRPC. Additional trials are planned to explore LYNPARZA in combination for the treatment of mCRPC regardless of HRR status. LYNPARZA was granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration in 2016 for the treatment of BRCA-mutated or ataxia telangiectasia mutated (ATM) gene-mutated mCRPC.

LYNPARZA is a first-in-class PARP inhibitor approved in the U.S. for certain patients with recurrent ovarian and metastatic breast cancer and has treated nearly 5,500 patients since 2014. LYNPARZA has a broad clinical development program, and AstraZeneca and Merck are working together to deliver LYNPARZA as quickly as possible to more patients across multiple cancer types, including prostate and pancreatic cancers.

Indications for LYNPARZA^® (olaparib) 100 mg in the U.S.

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

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.

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.

In patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously 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 treatment. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Important Safety Information for LYNPARZA^® (olaparib) tablets 100 mg

Contraindications

There are no contraindications for LYNPARZA.

Warnings and Precautions

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

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 (olaparib) if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, 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.

Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males

Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

Adverse Reactions—Maintenance Setting

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%). Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), and decreased appetite (21%).

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 adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA (olaparib) for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue (including asthenia) (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

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%), increase in mean corpuscular volume (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 Breast Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

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%).

Drug Interactions

Anticancer Agents: Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using LYNPARZA (olaparib). If a moderate inducer cannot be avoided, there is a potential for decreased efficacy of LYNPARZA.

Use In Specific Populations

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.

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 hepatic impairment (Child-Pugh classification A). There are no data in patients with moderate or severe hepatic impairment.

Renal Impairment: No adjustment to the starting dose is necessary in patients with mild renal impairment (CLcr=51-80 mL/min). In patients with moderate renal impairment (CLcr=31-50 mL/min), reduce the dose to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

About Study 08

Study 08 was a global, randomized, double-blinded, multi-center Phase 2 trial of 142 patients, assessing the efficacy and safety of LYNPARZA tablets (300 mg twice daily) and abiraterone tablets (4 x 250 mg once daily) (n=71) compared to matched placebo and abiraterone tablets (4 x 250 mg once daily) (n=71) in patients regardless of HRR status. Prednisone/prednisolone (5 mg twice daily) was administered to patients in both treatment arms.

Patients in Study 08 had previously received docetaxel for mCRPC. Prior to enrollment, patients had received no more than two lines of chemotherapy.

The primary endpoint was radiologic progression-free survival (rPFS) (time from randomization to radiologic progression or death). rPFS is increasingly used in clinical trials of mCRPC as a clinically-meaningful endpoint focusing on the impact of treatment on disease progression to areas where spread of prostate cancer is common, notably soft tissue and bone.

Secondary endpoints included time to second progression or death (PFS2), overall survival (OS) and health-related quality of life.

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. Metastatic castration-resistant prostate cancer (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 percent of men with advanced prostate cancer will develop mCRPC within five years, and at least 84 percent of these will have metastases at the time of mCRPC diagnosis. Of men with no metastases at mCRPC diagnosis, 33 percent are likely to develop metastases within two years. Despite an increase in the number of available therapies for men with mCRPC, five-year survival is only 28 percent.

About LYNPARZA^® (olaparib)

LYNPARZA was the 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. Specifically, in vitro studies have shown that LYNPARZA-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

LYNPARZA is being tested in a range of DDR-deficient tumor types.

About the AstraZeneca and Merck Strategic Oncology Collaboration

In July 2017, AstraZeneca and Merck, 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.

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Please see complete Prescribing Information for LYNPARZA (olaparib), including Patient Information (Medication Guide)

 

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