Recent discussions at the 2024 Advanced Prostate Cancer Consensus Conference (APCCC) have provided new insights into how PARP inhibitors can be best utilized in treating prostate cancer. The focus was on selecting appropriate patients and refining testing methods to maximize the benefits of these therapies while reducing long-term risks. Here’s a streamlined look at the key points as discussed by dr Johann De Bono:

• Genes Associated with PARP Inhibitor Sensitivity:
  Specific DNA mutations linked to PARP inhibitor efficacy include:
  • BRCA2: Biallelic loss of BRCA2 strongly predicts sensitivity.
  • PALB2 (BRCA3): Patients with biallelic loss or germline mutations often show prolonged responses.
  • ATM: Complete loss of ATM protein, though not an HRD gene, is linked to PARP inhibitor response.
  • FANCA: Rare, but complete loss can enhance PARP inhibitor efficacy.
  • RNASEH2B: Loss near RB1, observed in some prostate cancers, can sensitize tumors to PARP inhibitors.
  • CDK12: Alterations may lead to benefit, potentially through secondary hits on other DNA repair genes.

Despite these promising findings, several challenges remain. The current tests used to identify suitable candidates often produce unreliable results, with a significant risk of false positives or negatives. Functional assays that can more accurately detect DNA repair defects are urgently needed. Furthermore, many commonly used tests, which analyze so-called “archeological scars” in the tumor’s genetic material, do not perform well in prostate cancer, even if they have been effective in other cancers like ovarian cancer. Without more reliable testing methods, there is a real risk of treating patients who may not benefit while missing others who would.

Long-term safety is another pressing concern. There is evidence to suggest that prolonged use of PARP inhibitors could lead to secondary conditions, such as myelodysplasia or leukemia, similar to what has been observed with other DNA-damaging agents. This potential downside emphasizes the importance of careful patient selection and ongoing monitoring.

When PARP inhibitors are not accessible, alternative treatments like carboplatin may provide some benefit. However, it is crucial to note that patients who have progressed on PARP inhibitors are unlikely to respond to subsequent PARP1 inhibitors or platinum-based therapies due to the development of resistance mechanisms.

Note from the author of this article (from Max!):For the ATM gene, a complete loss—biallelic inactivation—is generally required for PARP inhibitors to be effective. In the context of cancer treatment, this usually means a somatic biallelic ATM mutation, because if such a mutation were germline, it would likely cause ataxia-telangiectasia. On the other hand, several studies suggest that combining an ATR inhibitor with a PARP inhibitor can effectively target various types of ATM mutations.

 Source.