18.5 clinical research - olaparib case study

3 subtypes of breast cancer and their prognosis

1. hormone receptor positive → responds to hormonal therapies

2. HER2 + → aggressive but treatable

3. triple negative (TNBC) → more difficult to treat, often linked to BRCA mutations

what is the standard treatment pathway for high-risk breast cancer

• neo-adjunvant chemotherapy (before surgery) + immunotherapy

• surgery + radiotherapy + endocrine therapy

1st line → tst treatment after diagnosis

2nd line → look at cancer progression

3rd line → chemoherapy

What is Olaparib and how does it work?

Olaparib is a PARP inhibitor (PARPi) that prevents the repair of single-strand DNA breaks. I

n BRCA-mutant cancer cells, which already have faulty DNA repair pathways, this leads to cell death via synthetic lethality.

Who is eligible for NHS genetic testing for BRCA mutations?

• Breast cancer < age 40

• Bilateral breast cancer < 50

• Triple negative breast cancer < 60

• Breast + ovarian cancer at any age

• Ashkenazi Jewish ancestry + breast cancer

• Male breast cancer

• Strong family history (e.g., < 45 with affected first-degree relative)

What were the main findings from the Phase 1 Olaparib trial (2005–2008)?

• Evaluated KU-0059436 (Olaparib) in 98 patients

• Focus: Safety, tolerability, and maximum tolerated dose (MTD)

• Some objective tumor responses were observed

What was the ICEBERG 1 Phase II trial?

study to assess the efficacy & safety of PARP inhibitor for treatment of BRCA-positive advanced breast cancer

Open-label, non-randomised

primary objective measure → confirmed objective tumour response

secondary outcome measure:

• duration of response

• clinical benefit

• best %change in tumour size

What were the results of the OlympiAD trial (Phase III)?

• Compared Olaparib (300mg BD) vs physician’s choice chemotherapy

• Enrolled 302 participants with BRCA-mutated metastatic breast cancer

• Olaparib significantly improved Progression-Free Survival (PFS)

• Open-label, randomised 2:1

What is the OlympiA trial and what did it show?

• Assessed Olaparib as adjuvant therapy in high-risk, HER2-negative BRCA+ breast cancer

• Enrolled 1836 patients

• Showed improved Invasive Disease-Free Survival (IDFS)

• Triple-masked (participant, provider, investigator)

What did NICE decide about Olaparib?

• Approved Olaparib for advanced BRCA-mutant breast cancer (TA1040)

• Approved as adjuvant treatment in early HER2- breast cancer (TA886)

• Introduced via commercial arrangement with AstraZeneca

What is the PARTNER trial and what did it investigate?

• Tested neoadjuvant chemotherapy with or without Olaparib in triple-negative or BRCA+ breast cancer

• No significant difference in pCR (pathological complete response) or event-free survival

• Validated “gap scheduling” as safe and adopted as UK standard

What is pCR and how is it measured?

• Pathological Complete Response (pCR) means no remaining cancer post-surgery

• Evaluated using the Residual Cancer Burden (RCB) index:

  • RCB0: Complete response

  • RCB1-3: Increasing levels of residual disease

• Strong correlation with Relapse-Free Survival (RFS)

What are some other trials combining Olaparib with other agents?

• Pembrolizumab + Olaparib

• Durvalumab + Olaparib

• Studies on combinations with platinum chemo, Atezolizumab, and CEDIRANIB

What are current research directions involving Olaparib?

• Combination with immunotherapies and other targeted drugs

• Use in other cancers beyond breast cancer

• Determining predictive biomarkers of response

• Exploring resistance mechanisms and post-PARPi progression strategies