The European Commission ( EC ) has approved Lynparza ( Olaparib ) as a 1st-line maintenance treatment for women with BRCA-mutated advanced ovarian cancer.
The licensed indication is as a maintenance treatment of adult patients with advanced ( FIGO stages III and IV ) BRCA1/2-mutated ( germline and/or somatic ) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response ( complete or partial ) following completion of 1st-line Platinum-based chemotherapy.
The EC approval was based on data from the pivotal phase III SOLO-1 trial which tested Olaparib as maintenance monotherapy compared with placebo in patients with BRCAm advanced ovarian cancer following 1st-line Platinum-based chemotherapy.
Results announced in October 2018 at 40.7 months of follow-up showed the median time of progression for patients treated with Olaparib had not yet been reached versus 13.8 months for those on placebo ( hazard ratio, HR 0.30 [ 95% CI, 0.23-0.41 ], p less than 0.001 ).
SOLO-1 was a randomised, double-blinded, placebo-controlled, multi-centre trial to evaluate the efficacy and safety of Olaparib tablets ( 300mg twice daily ) as a maintenance monotherapy compared with placebo in patients with BRCAm advanced ovarian cancer following first-line Platinum-based chemotherapy.
The trial randomised 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 randomised ( 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 SOLO-1 safety profile was in line with that observed in prior clinical trials.
The most common adverse events greater than or equal to 20% were nausea ( 77% ), fatigue ( 63% ), vomiting ( 40% ), anaemia ( 39% ) and diarrhoea ( 34% ).
The most common greater than or equal to grade 3 adverse effects were anaemia ( 22% ) and neutropenia ( 9% ).
Some 71% of patients on Olaparib remained on the recommended starting dose.
Additionally, 88% of patients on Olaparib continued treatment without an adverse effects-related discontinuation.
Ovarian cancer is a leading cause of cancer deaths in women worldwide, with a five-year survival rate of 19%.
In 2018, there were nearly 300,000 new cases diagnosed and around 185,000 deaths.
For newly-diagnosed advanced ovarian cancer, the primary aim of treatment is to delay progression of the disease for as long as possible and maintain the patient’s quality of life with the intent of achieving complete remission or cure.
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.
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 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. ( Xagena )
Source: AstraZeneca, 2019