LYNPARZA® (olaparib) in Combination With Bevacizumab, and as Monotherapy, Demonstrates Clinically Meaningful Long-Term Survival in Certain Patients With First-Line Advanced Ovarian Cancer in Exploratory Analyses of Two Phase 3 Trials

Five-year follow-up of the Phase 3 PAOLA-1 trial showed LYNPARZA plus bevacizumab provided a clinically meaningful improvement in overall survival in a subgroup of HRD-positive patients, with 65.5% of patients still alive versus 48.4% who received bevacizumab and placebo

The Phase 3 SOLO-1 trial demonstrated 67% of advanced ovarian cancer patients with BRCA mutations receiving LYNPARZA were alive at seven years versus 47% of placebo patients, the longest follow-up for any PARP inhibitor in this setting

RAHWAY, N.J.--(BUSINESS WIRE)--$MRK #MRK--AstraZeneca and Merck, known as MSD outside of the United States and Canada, today announced long-term follow-up results from the Phase 3 PAOLA-1 and SOLO-1 trials in first-line advanced ovarian cancer, which represent the longest-term data for any PARP inhibitor in this setting.

These results were presented on Sept. 9 at the European Society for Medical Oncology (ESMO) 2022 Congress, and the SOLO-1 results were published in the Journal of Clinical Oncology.

Ovarian cancer is one of the most common gynecologic cancers and has the worst prognosis and highest mortality rate. More than two-thirds of patients with ovarian cancer are diagnosed with advanced disease, and approximately 50-70% of these patients die within five years. Roughly half of patients with advanced ovarian cancer have homologous recombination deficiency (HRD)-positive tumors, including those with a BRCA mutation, and one in four women have a BRCA mutation.

Five-year follow-up and final OS results from Phase 3 PAOLA-1 trial (abstract #LBA29)

The Phase 3 PAOLA-1 trial evaluated LYNPARZA in combination with bevacizumab as first-line maintenance therapy in patients with advanced ovarian cancer, who were without evidence of disease after surgery or following response to platinum-based chemotherapy. Final overall survival (OS), a key secondary endpoint, in those who received LYNPARZA plus bevacizumab was 56.5 months versus 51.6 months with bevacizumab alone (HR=0.92 [95% CI, 0.76-1.12]; p=0.4118) in patients with newly diagnosed advanced ovarian cancer. These OS results were not statistically significant.

In an exploratory subgroup analysis of HRD-positive patients, LYNPARZA plus bevacizumab provided a clinically meaningful improvement in OS, reducing the risk of death by 38% (HR=0.62 [95% CI, 0.45-0.85]) versus bevacizumab alone. 65.5% of patients who received LYNPARZA plus bevacizumab were still alive at five years versus 48.4% who received bevacizumab alone. LYNPARZA plus bevacizumab also improved median progression-free survival (PFS) to nearly four years (46.8 months) versus 17.6 months with bevacizumab plus placebo, and 46.1% of patients who received LYNPARZA in combination with bevacizumab remain progression free versus 19.2% of patients who received bevacizumab alone. The safety and tolerability profile of LYNPARZA in this trial was in line with that observed in prior clinical trials, with no new safety signals. Adverse events of special interest for LYNPARZA in combination with bevacizumab versus bevacizumab alone included myelodysplastic syndrome/acute myeloid leukemia/aplastic anemia (1.7% vs. 2.2%), new primary malignancies (4.1% vs. 3.0%) and pneumonitis/interstitial lung disease/bronchiolitis (1.3% vs. 0.7%).

Seven-year follow-up from Phase 3 SOLO-1 trial (abstract #517O)

The Phase 3 SOLO-1 trial evaluated LYNPARZA as monotherapy as first-line maintenance therapy in patients with advanced ovarian cancer, who were without evidence of disease after surgery or following response to platinum-based chemotherapy. In the trial, LYNPARZA demonstrated a clinically meaningful improvement in OS versus placebo in patients with germline BRCA-mutated (gBRCAm) newly diagnosed advanced ovarian cancer, reducing the risk of death by 45% (HR=0.55 [95% CI, 0.40-0.76]; p=0.0004) versus placebo (not statistically significant). Median OS was not reached with LYNPARZA versus 75.2 months with placebo. At the seven-year descriptive OS analysis, 67% of LYNPARZA patients were alive versus 47% of placebo patients (44% of whom had a subsequent PARP inhibitor), and 45% of LYNPARZA patients versus 21% of placebo patients were alive and had not received a first subsequent treatment.

Additional data showed median time to first subsequent therapy (TFST) was 64.0 months with LYNPARZA versus 15.1 months with placebo. The safety and tolerability profile of LYNPARZA in this trial was in line with that observed in prior clinical trials, with no new safety signals. The most common treatment-emergent adverse events (≥20%) were nausea (78%), fatigue (64%), vomiting (40%), anemia (40%), diarrhea (35%), arthralgia (29%), constipation (28%), abdominal pain (26%), headache (23%), neutropenia (23%), dysgeusia (22%), dizziness (20%) and decreased appetite (20%).

Please see Important Safety Information for LYNPARZA after the “About SOLO-1” section below.

Professor Isabelle Ray-Coquard, principal investigator from the PAOLA-1 trial and president of the GINECO group said, “For women facing an advanced ovarian cancer diagnosis who are HRD-positive, a targeted treatment in the first-line maintenance setting is critical to helping them live longer. These latest results at the five-year landmark demonstrate that olaparib with bevacizumab reduces the risk of death by 38% in HRD-positive patients compared to bevacizumab alone, further reinforcing the clinically meaningful long-term survival benefit of this combination. This should be promising news for both clinicians and patients, as we see these additional data show that this combination may allow patients more time with family and loved ones. These results also highlight the importance of biomarker testing as part of a precision medicine approach to guide treatment decisions in ovarian cancer patients.”

Professor Paul Di Silvestro, investigator from the SOLO-1 trial and director of the program in women’s oncology at Women and Infants Hospital in Providence, Rhode Island, said, “The long-term results from SOLO-1 confirm that LYNPARZA continues to elicit a clinically meaningful improvement in overall survival in the first-line maintenance setting for more than seven years. Achieving long-term survival for patients with newly diagnosed advanced ovarian cancer is critical because the first-line setting offers the greatest potential to impact patient survival.”

Susan Galbraith, executive vice president, oncology R&D, AstraZeneca, said, “Historically, the five-year survival rate of newly diagnosed patients with advanced ovarian cancer is 30-50%. In that context, it is phenomenal to share the long-term overall survival data from both PAOLA-1 and SOLO-1, with two out of three patients still alive in these trials. We continue to believe in LYNPARZA’s ability to help biomarker-selected patients with advanced ovarian cancer to achieve better outcomes.”

Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories, said, “These latest data from the PAOLA-1 and SOLO-1 trials further highlight the importance of HRD testing, including for BRCA1/2 mutations, for all newly diagnosed advanced ovarian cancer patients at the point of diagnosis. Maintenance therapy with LYNPARZA may provide certain patients with HRD-positive or BRCA-mutated advanced ovarian cancer the opportunity to live longer.”

Summary of PAOLA-1 & SOLO-1 results

LYNPARZA is approved as maintenance treatment of platinum-sensitive relapsed ovarian cancer and as both monotherapy and in combination with bevacizumab for the first-line maintenance treatment of BRCAm and HRD-positive advanced ovarian cancer, respectively. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

About PAOLA-1

PAOLA-1 is a Phase 3, double-blinded trial evaluating the efficacy and safety of LYNPARZA added to standard-of-care bevacizumab versus bevacizumab alone as a first-line maintenance treatment for patients with newly diagnosed advanced FIGO stage III-IV high-grade serous or endometroid ovarian, fallopian tube or peritoneal cancer who had a complete or partial response to first-line treatment with platinum-based chemotherapy and bevacizumab. AstraZeneca and Merck announced in August 2019 that the trial met its primary endpoint of PFS in the overall trial population.

PAOLA-1 is an ENGOT (European Network of Gynaecological Oncological Trial groups) trial, sponsored by ARCAGY Research (Association de Recherche sur les CAncers dont GYnécologiques) on behalf of GINECO (Groupe d’Investigateurs National des Etudes des Cancers Ovariens et du sein). ARCAGY-GINECO is an academic group specializing in clinical and translational research in patients’ cancers and a member of the GCIG (Gynecologic Cancer InterGroup).

About SOLO-1

SOLO-1 is a Phase 3, randomized, double-blinded, placebo-controlled, multicenter trial to evaluate the efficacy and safety of LYNPARZA (300 mg twice daily) as maintenance monotherapy compared with placebo in newly diagnosed patients with advanced BRCAm ovarian cancer following platinum-based chemotherapy. The trial randomized 391 patients with a deleterious or suspected deleterious 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 (at the investigator’s discretion). The primary endpoint was PFS, and key secondary endpoints included time to second disease progression or death, TFST and OS. AstraZeneca and Merck announced in June 2018 that the trial met its primary endpoint of PFS in the overall trial population.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

There are no contraindications for LYNPARZA.

WARNINGS AND PRECAUTIONS

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in approximately 1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The median duration of therapy in patients who developed MDS/AML was 2 years (range: <6 months to >10 years). All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy.

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.

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 REACTIONS—First-Line Maintenance BRCAm Advanced Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥10% of patients who received 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%), urinary tract infection (13%), thrombocytopenia (11%), and stomatitis (11%).

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

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 REACTIONS—Maintenance Recurrent Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients who received 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 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 adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA in the adjuvant setting for OlympiA were: nausea (57%), fatigue (including asthenia) (42%), anemia (24%), vomiting (23%), headache (20%), diarrhea (18%), leukopenia (17%), neutropenia (16%), decreased appetite (13%), dysgeusia (12%), dizziness (11%), and stomatitis (10%).

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 adverse reactions (Grades 1-4) in ≥20% of patients who received LYNPARZA in the metastatic setting for 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 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 adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA in the first-line maintenance setting for POLO were: fatigue (60%), nausea (45%), abdominal pain (34%), diarrhea (29%), anemia (27%), decreased appetite (25%), constipation (23%), vomiting (20%), back pain (19%), arthralgia (15%), rash (15%), thrombocytopenia (14%), dyspnea (13%), neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and stomatitis (10%).

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 adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA for PROfound were: anemia (46%), fatigue (including asthenia) (41%), nausea (41%), decreased appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia (12%), cough (11%), and dyspnea (10%).

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%).

DRUG INTERACTIONS

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

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

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 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

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

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.

Media:
Melissa Moody, (215) 407-3536
Chrissy Trank, (640) 650-0694

Investor:
Peter Dannenbaum, (908) 740-1037
Damini Chokshi, (908) 740-1807