Sept. 18, 2020 10:45 UTC

KENILWORTH, N.J.--(BUSINESS WIRE)-- AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced positive five-year follow-up data from the Phase 3 SOLO-1 trial which demonstrated a long-term progression-free survival (PFS) benefit of LYNPARZA versus placebo as a first-line maintenance treatment in patients with newly diagnosed, advanced BRCA-mutated (BRCAm) ovarian cancer who were in complete or partial response to platinum-based chemotherapy.

Ovarian cancer is the eighth most common cause of cancer death in women worldwide and in 2018 there were nearly 300,000 new patients diagnosed and around 185,000 deaths globally. Approximately 22% of patients with ovarian cancer have a BRCA1/2 mutation.

Five-year follow-up data from the Phase 3 SOLO-1 trial showed LYNPARZA reduced the risk of disease progression or death by 67% (HR 0.33 [95% CI 0.250.43]), and improved median PFS to 56 months vs. 13.8 months for placebo. At five years, 48.3% of patients treated with LYNPARZA remained free from disease progression vs. 20.5% on placebo. The median duration of treatment with LYNPARZA was 24.6 months vs. 13.9 months with placebo. Median follow-up in the LYNPARZA arm was 4.8 years and 5 years for placebo.

The safety profile of LYNPARZA was consistent with previous observations in SOLO-1. The most common adverse reactions (ARs) 20% were nausea (77%), fatigue/asthenia (63%), vomiting (40%), anemia (39%) and diarrhea (34%). Grade 3 or greater ARs were reported in 40% of patients in the LYNPARZA arm with the most common being anemia (22%) and neutropenia (9%). ARs led to a dose interruption with LYNPARZA in 58% of patients and a dose reduction in 29% of patients. Twelve percent of patients on LYNPARZA discontinued treatment due to an AR.

Dr. Susana Banerjee, one of the investigators from the SOLO-1 trial and consultant medical oncologist at The Royal Marsden NHS Foundation Trust and reader at the Institute of Cancer Research, said, For patients with newly diagnosed BRCA-mutated advanced ovarian cancer, the benefit derived from two years of maintenance treatment with LYNPARZA continued long after treatment ended. At five years, almost half of these women had not progressed and were still living with stable disease. These results represent a significant step forward in the treatment of BRCA-mutated advanced ovarian cancer.

Dr. Jos Baselga, executive vice president, oncology R&D, AstraZeneca, said, Once a patients ovarian cancer recurs, it has historically been incurable. Even at an advanced stage, we have shown that maintenance treatment with LYNPARZA can help patients achieve sustained remission. Todays results further underline the critical importance of identifying a patients biomarker status at the time of diagnosis to be able to offer a maintenance treatment that may help delay disease progression for these patients.

Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, This is the first trial of a PARP inhibitor to read out a five-year follow-up and showed LYNPARZA improved progression-free survival to over four and half years versus 13.8 months with placebo following response to first-line platinum-based chemotherapy. This latest data represents a major and significant milestone in a disease which has historically had such a poor prognosis.

Summary of efficacy results

Progression-Free Survival

(Primary Endpoint)

Recurrence-Free Survival*

(Post Hoc Analysis)

LYNPARZA

N=260

Placebo

N=131

LYNPARZA

N=189

Placebo

N=101

Events, n (%)

118 (45)

100 (76)

79 (42)

74 (73)

Median, m

56.0

13.8

NR

15.3

HR (95% CI)

0.33 (0.250.43)

0.37 (0.270.52)

Patients progression or recurrence free at timepoint, % (Kaplan-Meier estimates)

These analyses are descriptive only; the SOLO-1 trial was not powered to assess a

statistical difference between treatment groups at these time points

1y

87.7 (N=212)

51.4 (N=65)

91.0 (N=159)

58.0 (N=56)

2y

73.6 (N=173)

34.6 (N=41)

77.2 (N=132)

39.0 (N=35)

3y

60.1 (N=129)

26.9 (N=30)

64.0 (N=99)

28.9 (N=25)

4y

52.3 (N=101)

21.5 (N=23)

55.2 (N=75)

23.0 (N=19)

5y

48.3 (N=58)

20.5 (N=16)

51.9 (N=42)

21.8 (N=12)

*Defined post hoc as time from randomization to disease recurrence or death. Patients had complete response at baseline based on electronic case report form data. CI, confidence interval; HR, hazard ratio; NR, not reached

The results were presented on Friday, Sept. 18, 2020, at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 (Abstract #811MO).

The Phase 3 SOLO-1 trial met the primary endpoint of PFS in June 2018, which formed the basis of approvals in the U.S., the EU, Japan, China and several other countries.

About SOLO-1

SOLO-1 was a Phase 3, randomized, double-blinded, placebo-controlled, multi-center trial to evaluate the efficacy and safety of LYNPARZA tablets (300 mg twice daily) as a maintenance monotherapy compared with placebo in newly diagnosed patients with BRCAm advanced ovarian cancer following response to first-line platinum-based chemotherapy. The trial randomized 391 patients with a deleterious or suspected deleterious germline or somatic BRCA1 or BRCA2 mutation who were in clinical complete or partial response following platinum-based chemotherapy.

Patients were randomized (2:1) to receive LYNPARZA or placebo for up to two years or until disease progression. Patients who had a partial response at two years were permitted to stay on therapy at the investigators discretion. The primary endpoint was investigator-assessed PFS and key secondary endpoints included time to second disease progression or death, time to first subsequent treatment and overall survival. The primary analysis results were presented at the 2018 ESMO Congress and published in The New England Journal of Medicine.

IMPORTANT SAFETY INFORMATION

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 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.

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 REACTIONSFirst-Line Maintenance BRCAm Advanced Ovarian Cancer

Most common adverse reactions (Grades 1-4) in 10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection/influenza/ nasopharyngitis/bronchitis (28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), UTI (13%), thrombocytopenia (11%), and stomatitis (11%).

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 REACTIONSFirst-Line Maintenance Advanced Ovarian Cancer in Combination with Bevacizumab

Most common adverse reactions (Grades 1-4) in 10% of patients treated with LYNPARZA/bevacizumab compared to a 5% frequency for placebo/bevacizumab in the first-line maintenance setting for PAOLA-1 were: nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%) and leukopenia (18%). In addition, the most common adverse reactions (10%) for patients receiving LYNPARZA/bevacizumab irrespective of the frequency compared with the placebo/bevacizumab arm were: diarrhea (18%), neutropenia (18%), urinary tract infection (15%), and headache (14%).

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 REACTIONSMaintenance Recurrent Ovarian Cancer

Most common adverse reactions (Grades 1-4) in 20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2 were: 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%), 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 REACTIONSAdvanced gBRCAm Ovarian Cancer

Most common adverse reactions (Grades 1-4) in 20% of patients in clinical trials of

LYNPARZA for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue/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%), 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 REACTIONSgBRCAm, HER2-negative Metastatic 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%).

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LYNPARZA (olaparib) Improved Median Progression-Free Survival to Over Four and a Half Years Compared to 13.8 Months with Placebo for Patients with...