Joshi Alumkal, MD, discusses treatment options for patients with metastatic castrate-resistant prostate cancer harboring homologous recombination deficient alterations, including PARP inhibitors.
oshi Alumkal, MD, Wicha Family Professor of Oncology, professor, Department of Internal Medicine, section head, Prostate and Genitourinary Medical Oncology, associate division chief, Basic Research, Division of Hematology-Oncology, member, the University of Michigan Rogel Cancer Center, director, Epigenetic Therapy, Michigan Center for Translational Pathology, discusses treatment options for patients with metastatic castrate-resistant prostate cancer (mCRPC) harboring homologous recombination deficient (HRD)alterations, including PARP inhibitors.
Genomic profiling studies have demonstrated the prevalence of homologous recombination repair (HRR) defects in mCRPC, Alumkal begins. Unlike hormone-naive prostate cancer, where such defects are less common, patients with mCRPC have a higher incidence of these genomic abnormalities, Alumkal states. This finding suggests two potential scenarios, he says: HRR mutations emerge as an adaptive mechanism in response to therapy or tumors prone to metastasizing or developing castration resistance inherently harbor HRR defects.
Emerging data indicate that approximately 20% of patients with mCRPC may have HRD tumors, Alumkal continues. Accordingly, several clinical investigations have been conducted to assess the efficacy of PARP inhibitors in this population. Tumor cells exhibiting HRR defects are unable to repair DNA via the normal double-stranded DNA repair process, Alumkal details. Consequently, these cells resort to utilizing PARP proteins for single-strand DNA repair. This disrupts the cell's single-stranded DNA repair mechanism, preventing effective DNA damage repair and often culminating in cell death, Alumkal explains.
Clinical trials focused on patients with mCRPC and HRR defects have consistently demonstrated that PARP inhibitors provide superior benefit compared with conventional treatment options, which include other androgen receptor signaling inhibitors (ARSIs) or chemotherapy agents, Alumkal reports. However, the therapeutic landscape has expanded to include radiopharmaceuticals like lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617) and Radium-223 (Xofigo), he adds. These new agents provide oncologists with additional tools to manage this challenging patient population.