Teaching pack: High-grade serous ovarian cancer

High-grade serous carcinoma arises in the fimbria of the fallopian tube and spreads across the peritoneum before it causes symptoms. Every tumour carries a TP53 mutation; about a fifth have a germline or somatic BRCA1 or BRCA2 mutation and roughly half are homologous recombination deficient, which makes them exquisitely sensitive to platinum and to PARP inhibitors. Standard care is complete cytoreductive surgery, before or after three cycles of carboplatin-paclitaxel, with bevacizumab in higher-risk disease, then maintenance: olaparib for BRCA-mutant tumours (SOLO-1), niraparib for all comers (PRIMA) or olaparib with bevacizumab for HRD-positive tumours (PAOLA-1). Secondary surgery helps selected patients at first relapse (DESKTOP III), and platinum-resistant disease has gained mirvetuximab soravtansine for folate receptor alpha-high tumours. Germline testing of every patient and risk-reducing salpingo-oophorectomy in carriers are part of the standard.

• PARP inhibitor maintenance has turned a disease that nearly always relapsed into one where a large fraction of BRCA-mutant patients remain disease-free seven years on.
• The fallopian tube origin has made opportunistic salpingectomy a population prevention strategy.
• Antibody-drug conjugates against folate receptor alpha are the first new active drugs in platinum-resistant disease in a decade.

1. 1996Carboplatin-paclitaxel becomes standard (GOG 111 and successors)
2. 2007Fallopian tube fimbria identified as the origin of serous cancer
3. 2011Bevacizumab improves progression-free survival (GOG-0218, ICON7)
4. 2014Olaparib: first PARP inhibitor approved
5. 2018SOLO-1: olaparib maintenance transforms BRCA-mutant first-line outcomes
6. 2019PRIMA and PAOLA-1 extend PARP maintenance beyond BRCA
7. 2022Mirvetuximab soravtansine approved for platinum-resistant disease

• Mirvetuximab soravtansine (treatment)
• Relacorilant (treatment)
• Folate receptor alpha (target)

• DESKTOP III / ENGOT-ov20 (phase 3, n=408): Overall survival: 53.7 months vs 46 months, HR 0.75
• SOLO-1 (phase 3, n=391): Progression-free survival: pending
• PAOLA-1 / ENGOT-ov25 (phase 3, n=806): Progression-free survival (HRD-positive): 37.2 months vs 17.7 months, HR 0.33
• PRIMA / ENGOT-OV26 (phase 3, n=733): Progression-free survival (HRD-positive): 21.9 months vs 10.4 months, HR 0.43
• SORAYA (phase 3, n=106): Objective response rate: 32.4%
• D9319C00001- 1L OC Mono Global RCT (phase 3, n=366): result not yet recorded

• No screening test lowers mortality.
• Homologous recombination proficient tumours gain little from PARP inhibitors.
• Platinum-resistant disease remains largely incurable.
• Access to HRD testing and PARP inhibitors outside high-income countries.

1. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
2. What is synthetic lethality and what is the proven clinical example?
   Answer

   Two genes where losing either alone is survivable but losing both kills the cell; tumours with BRCA loss die when PARP is inhibited, the basis of olaparib and other PARP inhibitors.
3. Who should have germline genetic testing when diagnosed with cancer?
   Answer

   All patients with TNBC, ovarian, pancreatic, or metastatic prostate cancer, increasingly all breast cancer, and anyone with suggestive family history; results change surgery, drug choice (PARP inhibitors), and family screening.

• Wikipedia: https://en.wikipedia.org/wiki/Ovarian_cancer
• Wikipedia: https://en.wikipedia.org/wiki/Ovarian_cancer