AstraZeneca’s Lynparza (olaparib) has been accepted for use within NHS Scotland by the Scottish Medicines Consortium (SMC) to treat adults with HER2-negative, locally advanced or metastatic breast cancer with germline BRCA1 or BRCA2 mutations after chemotherapy.

Breast cancer prevalence

In Scotland, nearly 5,000 people are diagnosed with breast cancer each year1. Mutations in the BRCA genes significantly increase the risk of developing breast cancer and are found in approximately 5-10% of all breast cancer patients2,3. Genetic testing is an essential part of the diagnosis and optimal care of patients with breast cancer4,5. Individuals with these mutations have a 50% chance of passing the gene variant to their children6. This makes BRCA mutations the leading cause of hereditary breast cancer cases7.

In the Scottish Northern Isles of Orkney and Shetland, it has been shown that just two gene variants account for nearly all (>90%) of the inherited cancer risk from BRCA variants8. This is a stark contrast to the situation in the general UK population, where over 350 variants would need to be tested to account for the same proportion of cancer risk from BRCA variants8. The evidence suggests an increased need for BRCA screening for people with familial risk factors in Scotland, versus the general population of the UK.

Professor David Cameron, Professor of Oncology at Edinburgh University and Director of Cancer Services at NHS Lothian, said: “Metastatic breast cancer is a challenging diagnosis for patients, who have to expect shortened survival, often experiencing low health-related quality of life, and a significant burden from its treatment. For those women whose breast cancer has arisen on a background of an inherited (germline) alteration in the BRCA1 or BRCA2 genes, olaparib offers patients a treatment option, with data from the OlympiAD Phase III trial, demonstrating a significant delay in cancer progression or death compared to standard chemotherapies, and to do so as a tablet therapy. This recommendation by the SMC represents a significant milestone for patients in Scotland, addressing an unmet need for targeted therapies for those living with BRCA-mutated HER2-negative breast cancer.”

SMC approval

The SMC regulatory decision was based on positive results from the pivotal OlympiAD Phase III trial9. In addition to meeting its primary endpoint of median progression-free survival (PFS) assessed by blinded independent central review (BICR), the trial showed that patients treated with olaparib had a 42% reduction in risk of their disease worsening or death (HR 0.58; 95% CI 0.43-0.80; p<0.001 median progression-free survival 7.0 vs 4.2 months) compared to those who received chemotherapy9. The safety profile of olaparib from the trial was consistent with the known safety profile of olaparib9.

Tom Keith-Roach, President of AstraZeneca UK, said: “This is a significant step forward for Scottish breast cancer patients with germline BRCA-mutations. We look forward to NHS Scotland expanding BRCA gene testing eligibility to this patient group.”

Olaparib for cancer treatment

Olaparib is a precision medicine and PARP (poly-ADP ribose polymerase) inhibitor, a targeted cancer therapy that helps damaged cells repair themselves10,11. As a cancer treatment, olaparib targets PARP to disrupt the DNA-repair process and potentially kill tumour cells11.

BRCA1 and BRCA2 are human genes that produce proteins that repair damaged DNA and play an important role in maintaining cells’ genetic stability12. When these genes become mutated, or altered, such that their protein product either is not made or does not function correctly, DNA damage may not be repaired, and these cells become unstable13. As a result, the cells are more likely to develop additional genetic alterations that can lead to cancer and confer sensitivity to PARP inhibitors including olaparib14,15,16,17.

The most common adverse reactions (≥20%) in the OlympiAD trial of patients who received olaparib were nausea (58%), anaemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhoea (21%), and headache (20%)9. The percentage of patients who discontinued treatment in the olaparib arm was 5% vs. 8% in the chemotherapy arm9.

References
  1. https://breastcancernow.org/about-us/why-we-do-it/breast-cancer-facts-and-statistics/
  2. https://breastcancernow.org/about-us/media/statements/we-respond-to-research-identifying-new-rare-genes-associated-with-breast-cancer/
  3. https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet
  4. Ahn S, et al. Genetic testing in patients with newly diagnosed breast cancer: Room for improvement. J Clin Oncol. 2017;35(20):2221-2223.
  5. Tung N, et al. Germline genetic testing for women with breast cancer: Shifting the paradigm from whom to test to whom NOT to test. J Clin Oncol. 2021;39(31):3415-3418.
  6. https://www.bebrcaware.com/resources/mutations#:~:text=Certain%20BRCA%20mutations%20are%20hereditary,family%20members%20regardless%20of%20gender.&text=or%20caregiver.,chance%20of%20inheriting%20the%20mutation
  7. Mehrgou A, et al. The importance of BRCA1 and BRCA2 genes mutations in breast cancer development. Med J Islam Repub Islam. 2016;30:369.
  8. https://viking.ed.ac.uk/research/two-founder-variants-90-percent-brca-alleles-orkney-shetland
  9. Robinson M. et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. New England Journal of Medicine, 2017;377:523-533.
  10. https://go.drugbank.com/drugs/DB09074. Last accessed February 2025
  11. https://www.cancerbrc.org/advance/olaparib-journey-world-first-drug
  12. https://www.england.nhs.uk/wp-content/uploads/2018/07/Genetic-testing-for-BRCA1-and-BRCA2-mutations.pdf
  13. Zámborszky, J. Loss of BRCA1 or BRCA2 markedly increases the rate of base substitution mutagenesis and has distinct effects on genomic deletions. Oncogene 36, 746–755 (2017).
  14. Roy R, et al. BRCA1 and BRCA2: Different Roles in a Common Pathway of Genome Protection. Nat Rev Cancer. 12(1):68-78.
  15. Wu J, et al. The Role of BRCA1 in DNA Damage Response. Protein Cell. 2010;1(2):117-123.
  16. Gorodetska I, et al. BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance. J Cancer. 2019;10(9):2109-2127.
  17. Li H, et al. PARP Inhibitor Resistance: The Underlying Mechanisms and Clinical Implications. Mol Cancer. 2020;19:107.