Performing specific tests to identify DNA alterations is increasingly decisive for choosing the most suitable option for each patient. Thus it is also possible to slow down the progression of advanced tumors
Slow down the growth of cancer in patients with prostate or ovarian cancer who have advanced cancer and who have had previous treatments, to gain valuable time and delay recurrence or further progression of the disease as much as possible. disease. This is the goal that many researches are aiming for when it is no longer possible to obtain healing olaparib, the parent molecule of the class of PARP inhibitors that has recently received a new approval from the Italian Medicines Agency (Aifa). Already in 2018, the addition of this drug to standard chemotherapy proved to be a very important innovative strategy for women with metastatic ovarian cancer at diagnosis capable of gaining several years of life without relapse. Now, after the confirmations of several trials involving thousands of patients, new indications are added for the use of this drug with the aim of obtaining long-term remission of the tumor in a larger number of patients.
What do prostate and ovarian cancers have in common
Cancers of the prostate (with about 36 thousand new diagnoses per year) and of the ovary (5,200 new cases) are, respectively, the most frequent malignancy in men in Italy and the tenth among women. Although for prostate cancer it has one of the best survivals (thanks to the often early diagnosis 5 years after diagnosis alive over 90% of patients), unfortunately that of the ovary is still among the most lethal with 5-year survival at 43%. , mainly due to the fact that about 80% of women discover the disease at an advanced stage, due to the lack of evident symptoms in the early stages. However, the two neoplasms may have one feature in common, namely alterations on a range of genes involved in DNA repair (homologous recombination defects, which include, for example, the BRCA1 and BRCA2 genes), capable of guiding the choice of treatment. Knowing the DNA mutations present in a patient’s neoplasm, the molecular characteristics of a single tumor, today fundamental for guiding therapeutic choices: target therapies, in fact, can only be used if the presence of specific markers is detected in the tumor cells.
Targeted therapies and genetic counseling
The identification of variants in the BRCA1 / 2 genes in a man with prostate cancer or in a woman with ovarian cancer – says Giovanni Scambia, scientific director of the Gemelli University Hospital Foundation in Rome – allows both to choose the most effective treatment for single case, is to undertake a path of oncogenetic counseling in family members to identify high-risk carriers. To the latter we can offer targeted programs for the early diagnosis of tumors associated with BRCA family transmission syndromes and strategies aimed at reducing the risk, such as surgical removal of tubes and ovaries. It has been estimated that, in a neoplasm such as that of the ovary, without effective screening tools, this approach can lead to a 40% reduction in the incidence in the next 10 years. The most recent Aifa approval concerns the reimbursement of olaparib in the treatment of patients with castration-resistant metastatic prostate cancer with BRCA1 / 2 gene mutation progressing after previous therapy with a new hormonal agent. Aifa also approved the reimbursement of olaparib in combination with bevacizumab, in the first-line maintenance treatment of advanced ovarian cancer with a homologous recombination defect (HRD), a defect in the repair mechanism of the DNA double helix present in about 50% of cases.
Ovarian cancer
In November 2020, the European Commission approved olaparib in combination with bevacizumab as maintenance after first-line chemotherapy for ovarian cancer, based on results from the Phase III PAOLA-1 study, published in the New England Journal of Medicine. The mix reduced the risk of disease progression or death by 67% – explains Nicoletta Colombo, director of the Oncological Gynecology Program of the European Institute of Oncology in Milan -. The addition of olaparib resulted in progression-free survival to a median of more than 3 years of 37.2 months compared to 17.7 with bevacizumab alone in patients with HRD-positive advanced ovarian cancer. We know that 70% of women with advanced disease relapse within two years: for this reason it is important to use maintenance therapies capable of achieving long-term remission. Data obtained with a 36-month follow-up also showed a statistically significant improvement in time to second disease progression, with a median of 50.3 months versus 35.3 months with bevacizumab alone. Today, experts have at their disposal effective therapies that allow even metastatic ovarian cancer to be kept under control for a long time. In addition to chemotherapy, there are antiangiogenic drugs, which prevent tumor growth and PARP inhibitors capable of acting selectively on the mutated cells that cause ovarian cancer. However, surgery is the first weapon against this neoplasm. In the initial stages of the tumor, there was a progressive increase in the use of minimally invasive, laparoscopic and robotic techniques, with a proven advantage in terms of tolerability – adds Scambia -. In advanced disease, the choice is made between primary surgery, that is, immediately after diagnosis, if the tumor appears completely removable, and interval surgery, preceded by neoadjuvant chemotherapy, if the neoplasm cannot be optimally eliminated at diagnosis. In case of relapse, optimal cytoreductive surgery in platinum sensitive disease has been shown to improve prognosis.
Perform tests for molecular alterations
The execution of the HRD test at the time of diagnosis assumes a fundamental role as it allows to promptly identify the patients who can benefit from a treatment capable of controlling the disease in the long term, delaying relapse, with a good quality of life. Mutations in the BRCA genes represent only a part of the defects of the homologous recombination system – underlines Colombo, who is also an Associate Professor at the Milano-Bicocca University -, which are found in about 50% of patients with newly diagnosed advanced ovarian cancer. and predict sensitivity to PARP inhibitors. Knowing the HRD status is fundamental for the selection of patients who can benefit from personalized first-line treatment with olaparib in combination with antiangiogenic drugs. The BRCA test, performed on peripheral blood or tumor tissue, also represents a fundamental step in the diagnosis and decision of the treatment of metastatic prostate cancer, as also established in the Recommendations of the Italian Association of Medical Oncology (Aiom). In fact, about 10% of men present a mutation of the BRCA genes, allowing to plan an adequate therapeutic path, thanks to the availability of an effective and well tolerated targeted therapy such as olaparib continues Giuseppe Procopio, head of the genitourinary medical oncology of the IRCCS National Institute Foundation of the Tumors of Milan.
Prostate cancer
The development of prostate cancer is often driven by the sex hormones, androgens, including testosterone. The metastatic form resistant to castration occurs when the tumor grows and spreads to other parts of the body, despite the administration of androgen deprivation therapy to block the action of male sex hormones – concludes Procopio -. in this context that Aifa has given the green light to olaparib as monotherapy. In the phase III PROfound study, olaparib more than tripled radiological progression-free survival, with a median of 9.8 months compared with 3 months with enzalutamide or abiraterone. And it reduced the risk of death by 31%, with a median overall survival of 19.1 months compared to 14.7 months with the hormone. Finally, the data on the quality of life are also favorable, a very important aspect to be considered especially in the metastatic phase.
April 5, 2022 (change April 5, 2022 | 10:51)
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