For World Ovarian Cancer Day on 8 May, Nicoletta Colombo, Associate Professor of the Milan Bicocca University and Director of the Gynecology Program at IEO, spoke at the live Facebook meeting organized by Acto Italia on 27 April.
“In the treatment of ovarian cancer, the PARP inhibitors used in the front line have given unexpected results both by increasing progression-free and overall survival, so unexpected that in some cases I would even speak of a potential cure from this tumour”- says Colombo.
The revolution of PARP inhibitors
Ovarian cancer, which affects 51,136 women in Italy with 5,370 new diagnoses a year (Globocan and Airtum 2022 data), is the gynecological neoplasm which, in recent years, has been at the center of a great diagnostic and therapeutic revolution. PARP inhibitors are the protagonists, target drugs that take advantage of the homologous recombination defect (Homologous Recombination Deficiency, HRD) associated with BRCA mutation (but not only), to block a further mechanism of DNA repair and cause cell death. It is estimated that 50% of women affected by high-grade serous ovarian cancer are HRD positive, which also includes the BRCA mutation, present in 25% of patients.
I PARP inhibitors, initially used in relapses, immediately showed good efficacy in delaying the relapses themselves. But it is only in the last 5 years, since 2018, when they began to be used on the front line, as maintenance therapy after chemotherapy, that the results have become particularly surprising especially in women with BRCA gene mutation and in those whose cancer is positive on the HRD test. The results of the last few months have confirmed a very important fact: not only does disease-free survival increase but also overall survival. This means that more women can now be treated and potentially healed. This was demonstrated by the SOLO1 study on patients with BRCA mutation: 7 years after diagnosis, 67% of patients treated with PARP inhibitors survive compared to 46% who did not receive them and 45% of patients had no relapses compared to 20 % who did not receive them.
Parp inhibitors and bevacizumab
Encouraging data also for HRD patients receiving the PARP inhibitor in combination with the antiangiogenic bevacizumab: 65% of the patients are alive 5 years after diagnosis compared to 48% of the women who did not receive the PARP inhibitor.
The results in BRCA and HRD negative women were also positive, albeit to a lesser extent. “It is therefore right to speak of a “positive PARP tsunami” – says Colombo – “due to the improvement that these drugs have brought to the patients’ prognosis”.
The HRD test in Italy
Reiterating the need to run tests BRCA e HRD upon diagnosis, Colombo clarifies that in Italy the test is not yet reimbursed by the NHS and is carried out using US technology, with difficulties in terms of response times and costs. To overcome this, the academic world in its laboratories, in Italy and in Europe, is developing an HRD test comparable with the one available in the United States and validated in the clinic and in the laboratory using samples from previous studies. Today some Italian centers can perform the tests in their laboratories also thanks to the support of the pharmaceutical industry. This way, these centers can get test results quickly and set up the right first-line therapy as well as run tests for other centers.
Relapse? New drugs coming
If the recurrence does occur, new therapies are emerging: antibody-drug conjugates. These are chemotherapy drugs linked to an antibody via linkers. The antibody recognizes a particular receptor on the tumor and carries the drug directly into the tumor itself which then internalizes it, with a “Trojan horse” effect. So instead of putting the chemotherapy drug into the bloodstream and hoping it will hit the tumor, the drug is delivered in a targeted manner, in high concentration and with greater efficacy. This mechanism is used in ovarian cancer with a drug already approved in the USA by the FDA, mirvetuximab soravtansine.
Immunotherapy and what comes next
Regarding immunotherapy, positive results are confirmed only in endometrial and cervical cancer. The results in the treatment of ovarian cancer remain disappointing, except for surprises from the combination of chemotherapy and pembroluzimab in platinum-resistant disease, currently under study.
In early June, the results of a study combining immunotherapy, chemotherapy, PARP inhibitors and bevacizumab will be officially presented at the ASCO Congress, the American Society of Medical Oncology.
At the immunotherapy level, the experience of recent years has suggested new approaches that use drugs based on the stimulation of the immune system and on cell therapy and which technology will help to build.
Can resistance to PARP inhibitors be fought?
Even PARP inhibitors do not escape the phenomenon of resistance. Women initially sensitive to this therapy, over time respond less and less, i.e. become resistant. How to overcome the problem? It can be tackled using combinations with antiangiogenic drugs or immunotherapies but also with other drugs that can restore the homologous recombination deficit and restore sensitivity to PARP inhibitors.
At the end of the event, Colombo concluded with a message of great optimism: “Even if it is not yet possible to heal all women, it is possible to give more life, often of good quality. Witness the increase in the number of women who live longer with the disease”.
Acto and World Ovarian Cancer Day
During the meeting, all the initiatives that the Acto Regionali (Piedmont, Lombardy, Triveneto, Tuscany, Campania, Puglia, Sicily) have in store to celebrate the XI World Day on Ovarian Cancer were presented (list attached) while Nicoletta Cerana reviewed Acto’s commitment over the past 10 years.
As you remember Nicoletta Cerana,President of Acto Italia – “World Day is an important moment of shared and global knowledge. I therefore invite everyone to help spread information about this tumor, because it is information the first weapon of defense that women have against this sneaky and complex neoplasm. World Day reminds everyone of the importance of getting to know her better and of undergoing regular checks.”