PARP inhibitors have become the standard of care for recurrent ovarian cancer after platinum-based chemotherapy. They can also be used earlier in the course of the disease, as studies show. Patients with BRCA mutations benefit particularly.
At the 11th International Charité Mayo Conference, Prof. Dr. Jonathan A. Ledermann gave an overview of the use of PARP inhibitors in ovarian cancer. Ledermann works at University College London Hospitals.
"This disease has had a poor prognosis for a long time," the oncologist reports. "We see in studies that the median progression-free survival with platinum-based chemotherapy with or without angiogenesis inhibitors is just 11 to 19 months." Ledermann adds, "About 70% of all patients with first-line treatment develop recurrences within three years." This shows the challenge oncologists face to improve treatment outcomes. But with PARP inhibitors, there is a silver lining.
The drugs have a completely different mechanism of action compared to these treatment strategies. They inhibit the enzyme poly-ADP-ribose polymerase (PARP). PARP is involved in the repair of single-stranded DNA breaks, such as those caused by cytostatic drugs. The aim of treating patients with PARP inhibitors is to prevent malignant cells from repairing defects in the genetic material themselves.
If there are also changes in the BRCA1 or BRCA2 genes, cancer cells become particularly sensitive to PARP inhibitors, because they no longer have the possibility to repair defects in the genetic material. Patients with ovarian cancer and BRCA mutation respond particularly well - this concerns about 50% of all cases.
In the meantime, there are numerous methodologically high-quality studies on PARP inhibitors, as Ledermann points out. Some examples: The randomised, placebo-controlled phase 3 study ENGOT-OV16/NOVA included patients with platinum-sensitive, recurrent ovarian cancer. If they had a germline BRCA mutation, their progression-free survival increased from 5.5 to 21.0 months compared to placebo. In women without this mutation, the value increased from 3.0 to 9.3 months.
The SOLO-2 study was a randomised, placebo-controlled phase 2 study. Patients with germline BRCA1/2 mutated ovarian cancer, fallopian tube carcinoma or primary peritoneal carcinoma were included. The median survival time was 51.7 months in the verum group and 38.8 months in the placebo group. After five years, 42.1% of all participants in the PARP group were still alive; in the placebo group it was 33.2%. Ledermann emphasises that overall survival is difficult to assess - both because of the long progression-free phases and because of the crossover design. From the placebo group, 38% of all women were transferred to the PARP group.
In the meantime, as Ledermann emphasises, there are several indications of benefit for other patient groups. In the randomised, placebo-controlled phase 3 PRIMA trial, oncologists investigated a PARP inhibitor as first-line therapy in patients who responded to platinum-based chemotherapy protocols. In the overall cohort, progression-free survival was 13.8 months versus 8.2 months. At the 24-month interim analysis, the researchers calculated overall survival to be 84% versus 77%. Patients with a specific defect in DNA repair, homologous recombination deficiency, benefited even more significantly. Their progression-free survival was 21.9 months versus 10.4 months with placebo.
Last but not least, scientists showed in PAOLA-1 that PARP inhibitors can be successfully combined with angiogenesis inhibitors. This randomised double-blind phase 3 trial enrolled women with newly diagnosed ovarian cancer. They received an angiogenesis inhibitor plus PARP inhibitor or plus placebo. The progression-free overall survival was 22.1 months in the group with both drugs, and only 16.6 months in the comparison group. All women were eligible to participate, regardless of BRCA mutation status.
"In general, PARP inhibitors are well tolerated," says Ledermann. All substances in the group showed a similar profile of side effects. In the haematological field, for example in severe anaemia, there are differences, he says. "Their activity is also similar," says the speaker. The advantage is that it is administered in tablet form; patients do not have to go to hospital.
Reference: 11th International Charité Mayo Conference, Presidial Lecture, 07.05.2021