Multicenter non-interventional study of prevalence of homologous recombination gene mutations and approaches to treatment of metastatic castration-resistant prostate cancer in Russia (ADAM)

Background. Prostate cancer (PCa) is one of the most common cancers of men. In 2022, 48,025 new PCa cases and 12,896 deaths from the disease were reported in Russia. Metastatic castration-resistant PCa still is one of the common causes of death in men.

Aim. To evaluate prevalence of homologous recombination repair gene (HRR) mutations in patients with metastatic castration-resistant PCa in Russia and to identify differences in clinical characteristics and treatment outcomes of patients with these mutations and without them.

Materials and methods. The study included 329 patients with metastatic castration-resistant PCa from 20 centers. Patients underwent molecular genetic analysis using next-generation sequencing to identify mutations in 14 HRR genes. The mutation status was determined in 3 routine laboratories and further validated in a central independent laboratory.

Results. The HRR gene mutations were detected in 59 (19.28 %) of 329 patients. The most common were ATM mutations – in 14 (4.57 %), BRCA2 – in 14 (4.57 %), BRCA1 – in 6 (1.96 %). All the patients received first-line therapy, with newgeneration antiandrogens and taxanes being used most frequently. The patients with HRR gene mutations had nearly

1.5 times lower median of progression-free survival (PFS) with first-line therapy: 12.8 months vs. 20.8 months in patients without mutations (p = 0.048). There was statistically significant difference in PFS between the observed groups with first-line therapy depending on the treatment group. In patients of general group having been treated with new-generation antiandrogen therapy, the median of PFS was 22 months, while in patients who had received taxanes it was 8.22 months (p <0.05). In patients with HRR gene mutations having been treated with first-line antiandrogenes of novel generation, the median of PFS was 20.5 months, while in patients without mutations the PFS median was 23.1 months (p = 0.14). In patients with mutations and having been treated with first-line taxanes, the PFS median was 6.15 months, while in patients without mutations it was 8.55 months (p = 0.4).

Conclusion. In our ADAM study in the Russian population, the proportion of carriers of the HRR gene mutations was slightly lower (19.28 %) than that reported in published randomized trials. There is also a different distribution structure and frequency of the most frequent mutations. Patients with the HRR gene mutations exhibited worse PFS rates and more aggressive course of the disease, which requires a special approach to treatment of this group of patients.

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