Impact case study database

First regulatory approvals of olaparib (trade name Lynparza). The ICR-led phase 1 and phase 2 trials (Ref. 1 and Ref. 2) resulted in further phase 2 trials of olaparib in ovarian cancer. The pivotal trial, Study 19, was performed in high-grade serous ovarian cancer patients with platinum-sensitive relapse. This study showed increased progression-free survival which was even more pronounced in patients with germline/somatic BRCA1/2 mutation, 11.2 months compared to 4.3 months. These results led to olaparib approval in December 2014 by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as a monotherapy for the maintenance treatment of women with BRCA1- or BRCA2-mutant high-grade serous ovarian cancer, or fallopian tube or primary peritoneal cancer, who have had either a complete or partial response to platinum-based chemotherapy [A]. In the EMA assessment report of olaparib [A] both ICR trials described above are presented in the table of 8 supportive clinical studies. The phase 1 trial (Ref. 1) is one of two phase 1 trials listed, Study 00002, and the phase 2 (Ref. 2) is one of two “Key Supportive” trials listed as Study 00012.

The inclusion of both BRCA1 or BRCA2 germline and somatically mutated tumours in the approvals made olaparib the first targeted treatment for an inherited cancer disorder. The National Institute for Health and Care Excellence (NICE) approval of olaparib in this indication followed in January 2016. The Appraisal Committee “concluded that a drug treatment that improves quality of life and extends periods of remission for patients with BRCA mutation- positive ovarian cancer would be highly valued by patients and their families.” [B]

Further regulatory approvals. The phase 3 SOLO-1 trial demonstrated that ovarian cancer patients treated with olaparib as first-line maintenance therapy experienced 3 more years of progression-free survival than those given placebo, a significant benefit not usually seen in oncology trials. “Women with ovarian cancer are often diagnosed with advanced disease, which unfortunately is associated with poor long-term survival rates. The newly-diagnosed setting is our best opportunity to achieve a sustained remission, since once a patient’s ovarian cancer recurs, it is typically incurable. The SOLO-1 results demonstrate the potential of Lynparza maintenance therapy earlier in the treatment pathway and reinforce the importance of identifying a patient’s BRCA mutation status at the time of diagnosis – these results could change the way we treat women with advanced BRCA-mutated ovarian cancer.” [C]

Based on the results of the SOLO-1 trial, olaparib has been approved in the EU, US, Canada, Japan and Brazil for first-line maintenance of germline/somatic BRCA1/2-mutated high grade epithelial ovarian cancer [D]. Olaparib is available on the NHS via the Cancer Drugs Fund as a first-line maintenance treatment. Each year, approximately 700 women in England with advanced ovarian cancer are expected to benefit from this new treatment option [E]. Based on the results from the PAOLA-1 phase 3 trial, olaparib was recommended for approval in EU as first-line maintenance treatment with bevacizumab for HRR-deficient advanced ovarian cancer in September 2020.

As of 2020, olaparib is approved in 78 countries for the treatment of ovarian cancer [F].

Impact in prostate cancer. Based on the results of TOPARP-A and B (Ref. 3 and Ref. 4), a phase 3 trial of the olaparib in mCRPC, the PROfound study, was initiated. Results from this trial showed a statistically significant and clinically meaningful improvement in the primary endpoint of radiographic progression-free survival with olaparib in men with mCRPC who have HRR gene mutation and have progressed on prior treatment (e.g. enzalutamide and abiraterone). Further results from the trial showed a statistically significant and clinically meaningful improvement in the key secondary endpoint of overall survival with olaparib versus enzalutamide or abiraterone in men with mCRPC selected for BRCA1/2 or ATM gene mutation [G].

Based on data from the PROfound study olaparib was approved by the FDA in May 2020 and by the EMA in November 2020 in BRCA mutant prostate cancer. Rucaparib, another PARP inhibitor was also approved by the FDA at the same time based on the results from TRITON-2. The rucaparib approval is an accelerated one, which will require the results to be replicated in a confirmatory trial. Olaparib remains the only PARP inhibitor to have demonstrated it can improve overall survival, versus enzalutamide or abiraterone for men with BRCA or ATM mutations.

Before the prostate cancer approvals, olaparib had already been used to treat more than 30,000 patients worldwide and this will only increase as there were approximately 1,300,000 new cases of prostate cancer diagnosed worldwide in 2018. Approximately 10-20% of men with advanced prostate cancer will develop mCRPC within five years and HRR gene mutations occur in approximately 20-30% of patients with mCRPC [H]. This therefore represents a large amount of patients that could benefit from olaparib treatment.

ICR research contributed to the understanding that approximately 20-30% of mCRPCs have mutations in HRR genes that may make them sensitive to PARP inhibitors (Ref. 5 and Ref. 6). As a consequence of this increased understanding and the importance of these findings, the National Comprehensive Cancer Network (NCCN) 2018 guidelines were updated to recommend consideration of testing mCRPC patients for germline and somatic mutations in DNA-repair genes ( BRCA1, BRCA2, ATM, PALB2, FANCA), and referring patients who have these mutations for genetic counselling. This information can be used to refer mCRPC patients with DNA-repair gene mutations “for early use of platinum chemotherapy, or eligibility for clinical trials (e.g. PARP-inhibitors)” [I].

Impact in other cancers. The first approvals of PARP inhibitors were in ovarian cancer but there has been impact in breast and pancreatic cancers. As of 2020, olaparib is approved in 76 countries for the treatment of metastatic breast cancer, and in 55 countries, including the US, for the treatment of pancreatic cancer [F].

Pharmaceutical industry impact. Olaparib was initially developed by the British company KuDOS, which was acquired by AstraZeneca in 2006. In 2020, AstraZeneca reported olaparib (Lynparza) sales of over USD1,776,000,000 worldwide compared to USD1,198,000,000 in 2019. The growth is in part as a result of regulatory approval for expanded uses in various cancers [F].