On June 3, 2019 AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) reported full results from the Phase III SOLO3 trial which compared Lynparza (olaparib) with physician’s choice of chemotherapy in the treatment of patients with germline BRCA1/2-mutated (gBRCAm) advanced ovarian cancer who had received two or more prior lines of chemotherapy (Press release, AstraZeneca, JUN 3, 2019, View Source [SID1234536798]).

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The results from the trial, presented at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, US, showed a statistically-significant and clinically-meaningful improvement in objective response rate (ORR) for Lynparza vs. chemotherapy (72.2% vs. 51.4% [95% CI, 1.40-4.58], p=0.002). ORR measures the proportion of patients with reduction in tumour burden of a predefined percentage.

The trial also met the key secondary endpoint of progression-free survival (PFS), demonstrating a statistically-significant and clinically-meaningful improvement in the time patients lived without disease progression for Lynparza (13.4 months) vs. chemotherapy (9.2 months [HR 0.62] p=0.013]).

José Baselga, Executive Vice President, Oncology R&D, said: "Lynparza provides a much-needed alternative and improvement over standard-of-care chemotherapy for patients with BRCA-mutated, advanced ovarian cancer. This is the fourth positive Phase II/III trial in advanced ovarian cancer for Lynparza, across multiple lines of therapy. We look forward to working closely with regulatory authorities to include findings from this trial in the prescribing information for Lynparza."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "Lynparza is the first and only PARP inhibitor to demonstrate efficacy versus chemotherapy in relapsed BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. The positive SOLO3 results reaffirm AstraZeneca and MSD’s ongoing commitment to explore potential treatment options beyond standard of care for BRCA-mutated with advanced stage disease."

Summary of resultsi

Lynparza
(300 mg bd)

Chemotherapy

ORR (primary endpoint)

Number of patients

151

72

Number of patients with response (%)

109 (72.2%)

37 (51.4%)

Odds ratio (95% CI)

2.53 (1.40, 4.58)

p-value

0.002

PFS (key secondary endpoint)i,ii

Number of patients

178

88

Number of patients with event (%)

110 (61.8%)

49 (55.7%)

Hazard ratio (95% CI)

0.62 (0.43, 0.91)

Median in months

13.4

9.2

p-value

0.013

iAssessed by blinded independent central review.

iiAnalysis was done at 59.8% maturity.

The safety and tolerability profile of Lynparza in the SOLO3 trial was consistent with previous trials. The most common adverse events (AEs) ≥ 20% were nausea (65%), fatigue/asthenia (52%), anaemia (51%), vomiting (38%), diarrhoea (28%), neutropenia (23%) and abdominal pain (21%). The most common ≥ Grade 3 AEs were anaemia (21%), neutropenia (10%), fatigue/asthenia (5%) and thrombocytopenia (4%). AEs led to dose interruption in 48% of patients on Lynparza while 7% of patients discontinued treatment.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, is approved for multiple indications in advanced ovarian cancer and metastatic breast cancer and has been used in over 20,000 patients worldwide.

About SOLO3

SOLO3 was a Phase III randomised, open-label, controlled, multicentre trial to evaluate the efficacy and safety of Lynparza tablets following two or more prior lines of chemotherapy. The trial randomised 266 patients with a deleterious or suspected deleterious BRCA1 or BRCA2 mutation. Eligible patients were randomised (2:1) to receive Lynparza 300mg tablets twice daily or physician’s choice of single-agent chemotherapy (paclitaxel, topotecan, pegylated liposomal doxorubicin or gemcitabine). The primary endpoint was ORR by blinded independent central review and key secondary endpoints included PFS, time to second disease progression or death and overall survival. The SOLO3 trial addresses a post-approval commitment from the December 2014 accelerated US approval of Lynparza in ovarian cancer.

About ovarian cancer

Ovarian cancer is a leading cause of cancer death in women worldwide, with a five-year survival rate of 19%.1 In 2018, there were over 295,000 new cases diagnosed and around 185,000 deaths.2 Over 70% of women with ovarian cancer have advanced disease at the time of diagnosis, with up to 80% at risk of recurrence after initial treatment.3 Effective treatments are needed in later lines of therapy as patients typically obtain limited benefit after two prior lines of chemotherapy.3

About BRCA mutations

Breast cancer susceptibility genes 1/2 (BRCA1 and BRCA2) are human genes that produce proteins responsible for repairing damaged DNA and play an important role maintaining the genetic stability of cells. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

About Lynparza

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR.

Lynparza is currently approved in over 60 countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer regardless of BRCA status. It is approved in the US, Canada and Brazil as 1st-line maintenance treatment of BRCAm advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in nearly 40 countries, including the US and Japan, for germline BRCAm HER2-negative metastatic breast cancer previously treated with chemotherapy; in the EU this includes locally advanced breast cancer. Regulatory reviews are underway in other jurisdictions for both ovarian cancer and breast cancer.

Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

About the AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise 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.