Platinum-sensitive ovarian cancer

Platinum sensitivity is a clinical state rather than a histology. A tumour that shrinks on carboplatin-paclitaxel and stays away for more than six months after the last cycle is likely to respond to platinum again, and the longer the platinum-free interval the better the response; most high-grade serous and endometrioid cancers begin in this state and drift towards resistance with each relapse. Biologically, sensitivity tracks homologous recombination deficiency: BRCA1 or BRCA2 mutation, found in about a fifth of high-grade serous tumours, and other defects that together mark about half, cannot repair the DNA crosslinks platinum causes, and the same defect makes them vulnerable to PARP inhibition. Germline and somatic BRCA testing and HRD testing are therefore standard at diagnosis.

Maintenance after first-line chemotherapy is the setting with the clearest gains. SOLO-1 gave two years of olaparib to women with BRCA-mutant tumours in response to platinum and cut the hazard of progression to 0.30; at seven years 67.0 percent were alive against 46.5 percent with placebo, a hazard ratio for death of 0.55 and the first sign that maintenance changes survival rather than delaying relapse. PRIMA extended niraparib to all comers with a progression-free survival gain from 8.2 to 13.8 months overall and from 10.4 to 21.9 months in HRD-positive tumours, though its final overall survival analysis showed no difference. PAOLA-1 added olaparib to bevacizumab maintenance and, in HRD-positive tumours, extended progression-free survival from 17.7 to 37.2 months with five-year survival of 65.5 percent against 48.4 percent. ATHENA-MONO confirmed the class with rucaparib. Which drug, whether to add bevacizumab, and whether HRD-negative tumours gain enough to justify treatment are decided by the tests.

At platinum-sensitive relapse, DESKTOP III showed that secondary cytoreductive surgery in women selected by a positive AGO score, complete resection at first surgery, good performance status and no ascites, extended median survival from 46.0 to 53.7 months when complete resection was achieved. Chemotherapy is a platinum doublet, carboplatin with pegylated liposomal doxorubicin, gemcitabine or paclitaxel, with bevacizumab in patients who have not had it, followed by PARP inhibitor maintenance if none was given before. Trials in relapse showed that PARP inhibitor maintenance after a later-line response delayed progression but did not improve survival in non-BRCA tumours and regulators narrowed those labels in 2022 and 2023, so the main benefit is now taken in the first line. Second PARP inhibitor exposure after progression, HRD-restoring reversion mutations and circulating tumour DNA to guide the duration of maintenance are the current research questions.