Teaching pack: Ovarian cancer

Ovarian cancer is a group of diseases (~320,000 new cases a year) dominated by high-grade serous carcinoma, which arises in the fallopian tube, is almost always TP53-mutant, and is diagnosed at stage III-IV in three-quarters of women because there is no symptom or screening test that catches it early. Roughly half of high-grade serous tumours have homologous recombination deficiency, including ~20% with germline or somatic BRCA1/2 mutations. Low-grade serous, endometrioid, clear-cell, and mucinous carcinomas are biologically distinct and respond differently to treatment.

The standard of care is maximal cytoreductive surgery (primary or interval, after neoadjuvant carboplatin-paclitaxel), sometimes with HIPEC, followed by maintenance therapy chosen by biomarker: olaparib for BRCA-mutated disease (SOLO-1, 7-year OS 67% vs 47%), olaparib plus bevacizumab for HRD-positive disease (PAOLA-1), niraparib for the rest with declining enthusiasm after PRIMA showed no survival gain. Platinum-sensitive relapse is treated with platinum doublets and secondary surgery in selected patients (DESKTOP III); PARP inhibitors are re-used less since later-line safety signals. Platinum-resistant disease, historically dismal, now has three new options with survival benefit: mirvetuximab soravtansine for FRα-high tumours (MIRASOL), relacorilant plus nab-paclitaxel (ROSELLA, approved 2026), and pembrolizumab plus weekly paclitaxel for PD-L1-positive tumours (KEYNOTE-B96, approved February 2026, the first immunotherapy in ovarian cancer). Low-grade serous carcinoma gained its first dedicated therapy in avutometinib plus defactinib (2025).

• PARP maintenance with 7-year OS benefit in BRCA (SOLO-1).
• First ADC (mirvetuximab) with OS benefit.
• Biomarker-directed maintenance after first-line chemotherapy: olaparib for BRCA (7-year OS 67% vs 47%), olaparib + bevacizumab for HRD-positive disease.
• Three new options with overall survival benefit in platinum-resistant disease within three years: mirvetuximab (FRα-high), relacorilant + nab-paclitaxel, and pembrolizumab + paclitaxel (PD-L1-positive, first immunotherapy approval in ovarian cancer, February 2026).
• First treatment designed for low-grade serous carcinoma (avutometinib + defactinib, May 2025).
• Surgery is evidence-based at both ends: HIPEC at interval debulking adds ~12 months of survival; selected secondary cytoreduction at relapse adds ~8 months.

1. 1976Cisplatin transforms ovarian cancer chemotherapy
2. 1994BRCA1 cloned; hereditary ovarian cancer explained
3. 1996Paclitaxel-cisplatin standard
4. 1996Paclitaxel-cisplatin becomes standard (GOG-111)
5. 2005Synthetic lethality of PARP inhibition in BRCA-deficient cells
6. 2007Fallopian tube identified as origin of high-grade serous cancer
7. 2011Bevacizumab improves PFS (GOG-0218, ICON7)
8. 2014Olaparib: first PARP inhibitor
9. 2014Olaparib: first PARP inhibitor approved
10. 2018SOLO-1 and OVHIPEC-1

• Raludotatug deruxtecan (product)
• Puxitatug samrotecan (product)
• PARP PET (technology)
• Galleri (product)
• Rinatabart sesutecan (product)
• RAINFOL-01 (Rina-S) (trial)
• Luveltamab tazevibulin (product)
• REJOICE-Ovarian01 (trial)
• Avutometinib + defactinib (product)
• WEE1 (target)
• ATR (target)
• Risk-reducing and opportunistic salpingectomy (technology)

• DESKTOP III / ENGOT-ov20 (phase 3, n=407): Overall survival: 53.7 months vs 46 months, HR 0.75
• OVHIPEC-1 (phase 3, n=245): Overall survival: 45.7 months vs 33.9 months, HR 0.67
• 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
• ATHENA-MONO / GOG-3020 (phase 3, n=538): Progression-free survival (ITT): 20.2 months vs 9.2 months, HR 0.52

• No effective screening.
• PARP resistance via BRCA reversion.
• Platinum-resistant disease remains lethal.
• No screening test reduces mortality (UKCTOCS); three-quarters of patients are still diagnosed at stage III-IV.
• Platinum resistance is eventually near-universal in high-grade serous disease, and each new drug adds months, not years.
• PARP inhibitor resistance (BRCA reversion, restored fork protection) has no approved counter; later-line PARP use has been curtailed by OS signals.

1. 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.
2. 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.
3. What questions should someone newly diagnosed with triple-negative breast cancer ask before surgery?
   Answer

   Whether chemo-immunotherapy before surgery (KEYNOTE-522) is planned and why; germline BRCA testing; PD-L1 and HER2-low status; TIL score; clinical trial options; fertility preservation; breast-conserving versus mastectomy and sentinel node approach; what response (pCR/RCB) will mean for treatment afterwards.
4. What are the main side effects of checkpoint inhibitors and how are they handled?
   Answer

   Immune-related adverse events such as colitis, thyroid problems, rash, hepatitis, and pneumonitis, most common with CTLA-4 plus PD-1 combinations; treated with steroids and sometimes other immunosuppressants, some endocrine effects are permanent.
5. What is the Galleri test and where does it stand with the FDA?
   Answer

   GRAIL's methylation-based multi-cancer early detection blood test for more than 50 cancers; PMA submitted January 2026 on PATHFINDER 2 and NHS-Galleri data, FDA advisory committee 23 September 2026. NHS-Galleri missed its primary stage III-IV reduction endpoint (stage IV fell ~14%).
6. What is positive predictive value and why does it matter for a cancer screening blood test?
   Answer

   The chance that a positive result is truly cancer. With a low-prevalence disease even a highly specific test yields many false positives; Galleri's PPV in PATHFINDER 2 was around 40-60%, so roughly half of positives lead to a diagnostic workup that finds no cancer.

• Wikipedia: https://en.wikipedia.org/wiki/Ovarian_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1453
• Guideline: https://pmc.ncbi.nlm.nih.gov/articles/PMC11163648/
• Guideline: https://www.nccn.org/guidelines/category_2
• Guideline: https://www.esmo.org/guidelines/guidelines-by-topic/gynaecological-cancers