Ovarian cancer remains deadly, with disappointing results from treatment. It is not often found before it has spread throughout the abdominal cavity (stage 3) or to distant organs (stage 4). Whilst there are benefits to aggressive surgery and chemotherapy, most patients will relapse within a year or 2. There is a correlation between the time to relapse and the response to further treatment.
Around 10 – 15% of ovarian cancers are associated with mutations in the patients’ BRCA genes, with further cancers being associated with mutations in the BRCA genes of the tumour itself. Patients with these mutations – despite being more prone to developing cancers – can show better responses to drug therapy than the remaining population. We already know that PARP inhibitors can prevent normal single-strand DNA breaks in cancer cells being repaired, leading to an increase in double-strand breaks. In cells with mutated BRCA (or similar), these breaks cannot be easily repaired which can stop the cancer dividing or lead to it being destroyed. Thus, BRCA-mutated tumours are expected to respond to PARP inhibition.
Drugs such as Olaparib and Niraparib are already in routine use in patients who have relapsed ovarian cancer. Last year, the SOLO1 study showed substantially delayed progression when Olaparib was used as a maintenance therapy after first-line chemotherapy for women with BRCA-mutated cancers. Thus, these drugs are proving beneficial in both the first-line and relapsed settings. Niraparib has also shown some benefit for women who do not have BRCA mutations.
Three other drugs have now been added to the first-line armoury. The PRIMA/ENGOT-OV26/GOG-3012 study looked at maintenance Niraparib therapy in patients regardless of BRCA status. The results showed a significant delay in progression for these patients.
The results appear even better in tumours which had mutations affecting DNA repair.
Veliparib is a less familiar drug in ovarian cancer treatment. Prof Coleman’s VELIA/GOG-3005 study has taken a slightly different approach than the authors of PRIMA and SOLO1; Veliparib being given alongside chemotherapy as well as in the maintenance phase. This approach mad the chemotherapy phase much more toxic with an increase in anaemia, low platelet counts, nausea and fatigue. It is going to take some time to sift through these data, but at present it isn’t clear that starting the PARP inhibitor therapy during the chemotherapy was better than waiting until the chemo was finished.
Nevertheless, the drug delayed the progression of cancer in both the population as a whole and especially in the group of patients who had BRCA mutations or defects in DNA repair.
If nothing else, it gives more reassurance that clinical benefits can be realised with PARP inhibitors regardless of BRCA status.
Such is the nature of Oncology that clinical trials are often outdated by the time they publish. SOLO1, PRIMA and VELIA all suffer that the comparator arms consisted of chemotherapy followed by observation only. In much of the world, the standard of care has changed to chemotherapy plus bevacizumab (a drug which targets a tumour’s blood supply) followed by maintenance bevacizumab. None of those trials can answer whether it is safe and effective to add PARP inhibitors for patients who are receiving bevacizumab.
Thus, the PAOLA-1/ENGOT-ov25 trial of maintenance Olaparib alongside bevacizumab is timely. Importantly, the combination appears to be safe. There was slightly more anaemia in the Olaparib patients but slightly less hypertension. Furthermore, there was a significant delay in progression on top of that achieved by the bevacizumab.
The gains were only seen in the patients with defective DNA repair in their tumours but they comprised a large proportion of the recruits.
We now have 3 good quality trials showing delayed progression of ovarian cancer when PARP inhibitors are used after first line chemotherapy, and evidence of benefit when used after first line chemo/bevacizumab and maintenance bevacizumab. It is less clear whether PARP inhibitors should be given alongside the chemotherapy.
None of these trials has yet shown that women actually live longer as a result of this treatment. This has been an elusive goal in ovarian cancer for decades now, with only a few hints here and there that more intensive treatment improves survival. There has to be hope, though, that survival benefit will be shown as these data mature. In the meantime, the case for PARP inhibition after first-line chemotherapy seems sound.