Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) has approved olaparib (Lynparza®; Merck, known as MSD outside the United States and Canada and AstraZeneca) as a maintenance treatment after first-line chemotherapy in patients with BRCA-mutated (BRCAm) ovarian cancer.
Worldwide, ovarian cancer is the eighth most-commonly diagnosed cancer and seventh most-common cause of cancer deaths in women. In Japan, an estimated 10,672 new cases were expected to be diagnosed in 2018, with approximately 5,215 deaths. For all types of ovarian cancer, the five-year relative survival is approximately 47%. For newly-diagnosed advanced ovarian cancer, the primary aim of treatment is to delay progression of the disease for as long as possible.
Breast cancer susceptibility gene 1/2 (BRCA1 and BRCA2) are human genes that produce proteins responsible for repairing damaged DNA and play an important role in 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.
First in class PARP inhibitor
Olaparib is a 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. Inhibition of PARP with olaparib 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. The drug is being tested in a range of tumor types with defects and dependencies in the DDR.
Olaparib, which is being jointly developed and commercialized by AstraZeneca and Merck (known as MSD outside the United States and Canada), has a broad and advanced clinical trial development program, and following their announcement in 2017, 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.
The collaboration between the two companies also includes a new drug called selumetinib, a MEK inhibitor, for multiple cancer types. AstraZeneca and Merck will develop olaparib and selumetinib in combination with other potential new medicines and as monotherapies. Independently, the companies will develop olaparib and selumetinib in combination with their respective PD-L1 and PD-1 medicines.
The approval in Japan was based on data from the randomized, double-blinded Phase III SOLO-1 trial (NCT01844986) which evaluated olaparib as maintenance monotherapy compared with placebo in patients with BRCAm advanced ovarian cancer following first-line platinum-based chemotherapy.
“This approval in Japan is a critical advance for women with ovarian cancer and a BRCA mutation,” noted Dave Fredrickson, executive vice-president, oncology at AstraZeneca.
“The goals of front-line therapy are long-term remission or a cure, yet currently 70% of patients relapse within three years of initial treatment. The progression-free survival benefit of olaparib observed in SOLO-1 represents a major step forward in our ambition to improve patient outcomes,” Fredrickson observed.
“Advances in understanding the role of BRCA mutations and PARP inhibition have fundamentally changed how physicians can treat this aggressive type of cancer,” aded Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories.
“With the approval of this new indication, patients in Japan with BRCA-mutated advanced ovarian cancer who respond to chemotherapy will have the opportunity to benefit from olaparib in the first-line maintenance setting,” Baynes concluded.
Results from the SOLO-1 trial showed that olaparib reduced the risk of disease progression or death by 70% versus placebo following response to platinum-based chemotherapy (HR 0.30 [95% CI 0.23-0.41], p<0.001).
Olaparib is the only PARP inhibitor approved in Japan. AstraZeneca and Merck are exploring additional trials in ovarian cancer, including the ongoing Phase III PAOLA-1 trial, which is testing olaparib in combination with bevacizumab as a first-line maintenance treatment for women with advanced, stage IIIB-IV high-grade serous or endometrioid, fallopian tube or peritoneal ovarian cancer, regardless of BRCA status.
SOLO-1 was a Phase III, randomized, double-blinded, placebo-controlled, multi-center trial to evaluate the efficacy and safety of olaparib tablets (300 mg twice daily) as maintenance monotherapy compared with placebo in patients with BRCAm advanced ovarian cancer following 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 olaparib 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 investigator’s discretion. The primary endpoint was progression-free survival (PFS) and key secondary endpoints included time to second disease progression or death, time to first subsequent treatment and overall survival.
The data were presented on October 21, 2018, at the Presidential Symposium of the European Society for Medical Oncology (ESMO) Congress in Munich, Germany and published simultaneously online in the New England Journal of Medicine (NEJM) 
|Summary of PFS (a, b)|
|Olaparib (n=260)||Placebo (n=131)|
|Number of patients with event (%)(c)||102 (39)||96 (73)|
|Median (in months)||Not reached||13.8|
|Hazard ratio (95% CI)||0.30 (0.23-0.41)|
(b) Median (interquartile range) duration of follow-up 40.7 months (34.9–42.9) for Lynparza and 41.2 months (32.2–41.6) for placebo
(c) Analysis was done at 50.6% maturity
The SOLO-1 safety profile was in line with that observed in prior clinical trials. The most common adverse events (AEs) ≥ 20% were nausea (77%), fatigue (64%), vomiting (40%), anemia (39%) and diarrhea (34%). The most common ≥ Grade 3 AEs were anemia (22%) and neutropenia (8%). Seventy-one percent of patients on olaparib remained on the recommended starting dose. Additionally, 88% of patients on olaparib continued treatment without an AE-related discontinuation. Further, 48% of patients on olaparib did not have a dose interruption as a result of an Adverse Events.
 Olaparib Maintenance Monotherapy in Patients With BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy. (SOLO-1) – (NCT01844986)
 Platine, Avastin and OLAparib in 1st Line (PAOLA-1) – NCT02477644
 Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, Lisyanskaya A, Floquet A, et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2018 Dec 27;379(26):2495-2505. doi: 10.1056/NEJMoa1810858. Epub 2018 Oct 21. [PubMed]
 Spriggs DR, Longo DL. Progress in BRCA-Mutated Ovarian Cancer. N Engl J Med. 2018 Dec 27;379(26):2567-2568. doi: 10.1056/NEJMe1812644 [PubMed]