PARP inhibitors (PARPi)—targeted therapies that make cancer cells more vulnerable by blocking their ability to repair DNA—have been a breakthrough treatment for certain men with advanced prostate cancer, particularly those with mutations in DNA repair genes like BRCA2, ATM, and CHEK2. While these drugs can slow cancer progression, many patients eventually relapse and are left with few treatment options.
Results of a new MCW study, now published in Clinical Genitourinary Cancer, showed that platinum-based chemotherapy may be effective when first-line therapies fail. After analyzing genetic data from patients who progressed on PARPi, investigators discovered those with BRCA2 mutations were more likely to respond to this older class of chemotherapy. Deepak Kilari, MD, Associate Professor of Hematology and Oncology, and co-first author of the study, said the findings offer a potential new treatment option while bringing the field closer to more precise, genetic-driven strategies tailored to individual patients.
“This treatment approach not only provides an additional line of defense but also highlights our commitment to moving the needle on personalized cancer care, ensuring prostate cancer therapies are tailored to the unique genetic profiles of each patient,” said Dr. Kilari.
To investigate whether platinum-based chemotherapy could benefit patients after PARPi resistance, researchers reviewed the medical records of nine men with metastatic castration-resistant prostate cancer who had previously received PARPi but whose cancer progressed. As part of their care, these patients had genetic testing that identified mutations in DNA repair genes. Four were treated with Carboplatin. The key findings showed:
- Three out of four patients with BRCA2 mutations had a decline in prostate-specific antigen (PSA) levels—a key marker used to track prostate cancer activity—indicating a response to platinum therapy.
- One patient with ATM and CHEK2 mutations had minimal response, suggesting some genetic profiles may not benefit.
- Patients receiving both Carboplatin and another chemotherapy drug, Cabazitaxel, appeared to do better, though the exact contribution of each drug is unclear.
Investigators noted that these responses may be linked to defects in the homologous recombination repair (HRR) pathway, which helps fix damaged DNA. “Up to 20% of men with prostate cancer have HRR mutations, making their tumors more vulnerable to DNA-targeting treatments like PARPi and platinum chemotherapy. However, not all patients respond the same way, highlighting the need for better predictors of treatment success,” explained Dr. Kilari.
“These case study series provide early indications that in a significant subset of HRR pathway mutant cases, resistance to PARPi does not necessarily confer resistance to platinum-based therapies. In other words, the mechanisms of resistance to PARPi do not necessarily eliminate platinum sensitivity in HRR-mutated patients,” said Navonil De Sarkar, PhD, Assistant Professor of Pathology, and co-author of the study.
Prostate cancer is the most common cancer among men in the U.S., with African American men facing worse outcomes due to limited healthcare access, lower insurance rates, and barriers to screening and early detection. At MCW, researchers are leveraging genetic insights to match patients with treatments tailored to their cancer’s biology, moving beyond the usual one-size-fits-all approach. By expanding access to these advancements, particularly in underserved communities, MCW is working to close gaps in care and improve outcomes for those most at risk.
“We’re now identifying predictors of response to platinum-based chemotherapy after PARP inhibitor resistance, which could help guide treatment decisions and improve outcomes for men with advanced disease,” said Dr. Kilari.
Read the full study in Clinical Genitourinary Cancer.