New drugs improve survival

PARP (polyADP ribose polymerase) inhibitors are a new class of drugs that modify the therapeutic arsenal of ovarian cancers. Until now we had chemotherapies for the first line treatment (paclitaxel and carboplatin), such as that of recurrences (mono or polychemotherapy based on platinum or not depending on the time of onset of the recurrence, previous treatments and their possible toxicities ). Since 2012, bevacizumab (AVASTIN), concomitant with chemotherapy then in maintenance, completes these treatments, either in first line or at the time of a recurrence. It provided a notable improvement in disease-free time (PFS) during initial treatment, but not in overall survival.

PARP inhibitors use a different mechanism of action than previous drugs. High-grade serous cancers frequently include a gene mutation that participates in one of the main DNA repair mechanisms (homologous recombination). The best known are the two BRCA 1 and 2 genes, but others have been identified more recently (RAD51, PALPB2, etc.). PARP inhibitors, by blocking the other important repair pathway, prevent the cell from repairing DNA and cause its death. We deduce that these drugs will be especially effective in case of germline (of the individual) or somatic (of the tumour) mutation of one of these genes.

PARP inhibitors are effective in platinum-sensitive recurrences.
Study 19 (Ledermann J & al 2014), then the SOLO study 2 (Pujade Lauraine E & al 2017) showed that olaparib (LYNPARZA) significantly improved the PFS of patients treated for a platinum sensitive recurrence of a high-grade (or related) serous cancers. The SOLO 2 study included patients with a BRCA gene mutation, platinum-sensitive recurrence and who had responded to platinum chemotherapy. Maintenance with olaparib, given orally, thus increased the PFS from 5.5 months to 19.1 months (HR 0.30). The tolerance was found to be acceptable. The main side effects were nausea, fatigue, vomiting, abdominal pain or diarrhea. Treatment only had to be interrupted in 11% of cases. This medicine now has marketing authorization for this indication. Another drug of the same class (niraparib, ZEJULA), given in the same indication as olaparib in the NOVA study, provides the same result with a significant improvement in PFS and an acceptable tolerance (Mirza M & al 2016) . This drug has also shown efficacy in patients without known BRCA gene mutations, although the difference with placebo is smaller than in patients with BRCA mutations. This drug has a Marketing Authorization for patients with a sensitive relapse. Rucaparib (RUBRACA), another PARP inhibitor, provides similar results in the ARIEL3 study (Coleman R & al 2017). This medicine is now available in France.
It should be noted that these drugs are used in the event of “platinum sensitive” recurrence of high-grade serous cancers (with BRCA gene mutation for some), having responded to a second line of platinum chemotherapy. This is maintenance treatment given over several months or years.

In 2018, the SOLO 1 study (Moore K & al 2018) provided major results for first-line treatment. This trial included patients newly treated for high-grade (or related) serous cancer, carrying a BRCA 1 or 2 gene mutation. The treatment was given at the end of chemotherapy, for a period of 2 years. (or until progress). Patients who received olaparib benefited from a significant increase in their progression-free survival (an additional 36 months compared to patients without olaparib). Other survival parameters were also improved.
These results will radically change the treatment of patients with high-grade serous cancer at an advanced stage. The search for somatic or germline mutation becomes necessary from the start of treatment in order to be able to discuss the use of olaparib in maintenance of the first chemotherapy. This involves the organization of rapid circuits for the diagnosis of BRCA gene mutations, thanks to collaboration between clinicians, geneticists and molecular biology platforms which already exists and which will be reinforced by the national GREAT programme. The early identification of patients carrying such mutations has become essential for the treatment of their disease. It is also essential to diagnose germline mutations of the BRCA genes to advise patients on screening for other cancers favored by this predisposition as well as for the search for the BRCA1 or 2 mutation in their relatives.