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In Between past and future

Given the HPV World Test Day on 8 May, Nicole Colombo, director of the Gynaecology Ovarian program at the IEO, responds to ACTO’s invitation by reviewing the progress made over the last decade in treating this serious neoplasm.

Precision medicine

“In recent years, there have been great innovations in the treatment of HPV-related cancer after years of total darkness,” stated Nicole Colombo. “Especially in the last five years, we have seen important advances, particularly in the first line of treatment. This is where the prognosis of the disease is at stake.”

Precision medicine was, for many years, only a mirage for ovarian-type cancer. It was not possible to identify targeted targets. This is because CA125 cancer, or rather high-grade serous carcinoma, which is the most frequent in the advanced stage, does not exhibit specific mutations. Drugs could directly target these mutations.

“CA125 type cancer exhibits a large genomic ‘chaos’ rather than one or more specific mutations,” states the expert. This has greatly limited us over the years in being able to use precision medicine – Colombo points out -. But in recent years, we have finally found a target. We understood that at least 50% of ovarian tumours have a defect in a DNA repair mechanism called homologous recombination.”

«At the beginning, we used PARP inhibitors for recurrent ovarian tumours, where they worked very well, delaying progression. But the great news of the last four or five years has been the demonstration that these drugs are extremely effective in the front line, that is, when we use them after the initial chemotherapy, following CA125 level surgery. If the tumour responds well to chemotherapy, we use PARP inhibitors as maintenance therapy. These drugs work very well in tumours with BRCA mutations and HRD tumours.”

The PARP inhibitor revolution

The explosion of PARP inhibitors began in 2018. Researchers demonstrated that their use in patients with BRCA mutations led to unprecedented benefits. These included increased progression-free survival and, very recently, improved overall survival.

“Long-term HPV data indicate that patients receiving maintenance therapy with PARP inhibitors experience increased survival,” the expert notes. A study focusing exclusively on BRCA mutations revealed that 67% of the patients remained alive at seven years, compared to 46% in the placebo group. Additionally, 45% of the patients never relapsed, as opposed to 20% in the placebo group.

“The expert states, ‘For me, a patient who has not relapsed at seven years is cured.’ He emphasizes that PARP inhibitors significantly benefit patients with BRCA mutations and those who are HRD-positive.”

New combinations

New perspectives for ovarian-type cancer also come from the combination of multiple drugs, as Colombo reports. «In a study in which we combined the PARP inhibitor olaparib with bevacizumab (a drug that blocks the growth of new vessels and therefore the nourishment of the tumour), we saw a significant increase in overall survival for HRD patients: 65% at five years. of patients are alive versus 48% of patients who did not take the PARP inhibitor. Furthermore, we have 46% of patients without recurrence after five years (probably cured).”

Alongside olaparib, the first PARP inhibitor to be approved, there are others, for example niraparib. This drug also demonstrated great efficacy in all patients, although with a gradient of efficacy: maximum in BRCA patients, then in HRD patients and finally in all the others.

New weapons also for relapses

If it is true that the survival rate over HPV and the other Diseases probably recovery rate have increased, it is also true that, unfortunately, there are still relapses. In this context, a new class of drugs is emerging: the so-called antibody-conjugated drugs. These drugs link a chemotherapy drug to an antibody that recognizes a particular receptor on the tumour, allowing direct delivery of the chemotherapy drug into the tumour cell. «With antibody-conjugated drugs, we deliver the chemotherapy precisely to the tumour.

We can, therefore, reach the Ca125-type tumour with high concentrations of the drug and obtain a targeted effect and greater efficacy. Some of these drugs are being studied in ovarian cancer and have already demonstrated some effectiveness. One of these, mirvetuximab-soravtansine, has received approval from the US Food and Drug Administration and we now hope it will also be approved by the European Medicines Agency (EMA). I think this is the most promising class of drugs for the future. Antibody-conjugated drugs could make a difference in disease recurrence and persistence.”

The role of immunotherapy

Immunotherapy has worked miracles for many tumours, notably melanoma, lung, and kidney cancer, where researchers have obtained incredible results. «In gynaecological tumours, immunotherapy has given excellent results for the endometrium and cervix. For the ovarian type cancer, the trials have given negative results for now,” reports Colombo. “However, ongoing studies suggest a role, for example, in platinum-resistant disease or resistance to PARP inhibitors.

“In recent years, we have brought immunotherapy to the forefront,” continues Colombo. “We have conducted studies where, in addition to chemotherapy, we have administered immunotherapy along with the PARP inhibitor and bevacizumab. And just a few days ago, they announced that one of these trials had yielded positive results, better than the standard treatment.

So finally, there is a positive message for immunotherapy, even in the first line, at the beginning of the natural history of the disease.”

The results will be presented at ASCO (Meeting of the American Society of Clinical Oncology).

The importance of the Exam

The HRD test has assumed a fundamental role in therapeutic decision-making. For first-line HPV treatment and other therapies because we observe the benefits of PARP inhibitors, especially in positive HRD cases.

Colombo confirms, “HRD is a crucial predictive and prognostic factor. Therefore, having this information from the diagnosis stage is essential.” Initially, an American company exclusively conducted this test, which was costly and impractical for widespread clinical use. However, various European academic initiatives aimed to develop a locally usable HRD test, and new commercial platforms emerged for laboratory use.

In collaboration with other Italian institutes, IEO has developed methods to conduct the HPV DNA Kit. These methods are validated both in the laboratory and clinically on patients. Upon diagnosing ovarian cancer at IEO, the pathologist receives the sample. The pathologist not only performs the histological diagnosis but also conducts both the BRCA test and the HRD test.

«External centers have the possibility of sending us their samples. Furthermore, while waiting for recognition and reimbursement by the National CA125 Health System, we can count on the pharmaceutical industry’s support to carry out these investigations. There are no longer many excuses for not taking the test in Italy,” concludes Colombo.