BRCA mutation

While next-generation androgen receptor signaling inhibitors (ARSIs), such as enzalutamide and abiraterone, have revolutionized CRPC treatment, resistance to these therapies remains a significant challenge, rendering the disease incurable. Compelling evidence further suggests that combining PLK1 inhibition with paclitaxel could serve as an effective therapeutic strategy to overcome resistance in CRPC by targeting microtubule dynamics. This review examines the mechanistic role and broader implications of PLK1 in CRPC treatment, offering valuable insights into potential combination therapies to improve efficacy and patient outcomes.

Finally, we summarize current challenges-including limited accessibility, resistance mechanisms, and toxicities-and outline future directions, such as novel biomarkers, liquid biopsy for real-time resistance monitoring, and innovative adaptive trial designs. This review highlights the evolution of DDR-targeted therapy in pancreatic cancer toward personalized, combination-based precision medicine.

P=N/A, N=524, Active, not recruiting, Weill Medical College of Cornell University | Recruiting --> Active, not recruiting | N=820 --> 524 | Trial primary completion date: Mar 2026 --> Sep 2025

Tucatinib-based combinations and trastuzumab deruxtecan have demonstrated substantial intracranial activity in prospective trials, shifting the treatment paradigm by supporting systemic therapy even in the presence of active brain metastases. A major limitation remains the underrepresentation of patients with brain metastases in clinical trials. This review summarizes current evidence on systemic therapies for BCBM across subtypes and highlights the need for CNS-inclusive trials and the development of effective CNS-active treatments.

P=N/A, N=75, Not yet recruiting, AstraZeneca

After neoadjuvant chemotherapy with paclitaxel, carboplatin, and bevacizumab, followed by interval debulking surgery and postoperative chemotherapy, she achieved a complete response and began maintenance therapy with bevacizumab plus olaparib. This case highlights a previously unreported ocular adverse event associated with combined PARP inhibitor and anti-VEGF maintenance therapy. Clinicians should maintain vigilance for visual symptoms and consider periodic ophthalmologic monitoring in patients receiving prolonged olaparib-based therapy.

Using MyChoice CDx as reference, commercially available assays showed concordance in detecting HRD, genomic instability, and BRCA mutations, indicating their potential clinical utility in identifying appropriate treatment options for ovarian cancer.

Fuzuloparib plus AA-P had an acceptable safety profile and showed promising efficacy among mCRPC patients.

P1/2, N=31, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2029 --> Dec 2028 | Trial primary completion date: Jun 2026 --> Jun 2028

PARP inhibitor (olaparib and niraparib) maintenance therapy yields favorable clinical outcomes for elderly ovarian cancer patients. Three clinical factors, attainment R0(no residual disease) after initial surgery, BRCA mutation, and CA-125 ≤10 U/mL before PARP inhibitor treatment, were predictive of longer PFS in elderly ovarian cancer patients undergoing first-line maintenance therapy with PARP inhibitors.

The substantial hereditary and potentially actionable molecular burden supports universal germline testing and comprehensive tumour genomic profiling, particularly in younger patients and in KRAS wild-type disease. PARP inhibitors should be described as improving progression-free survival or disease-control outcomes in selected BRCA-mutated metastatic PDAC rather than as having established a statistically significant overall survival benefit.

Agents such as olaparib, talazoparib, and niraparib have demonstrated promising efficacy in both neoadjuvant and adjuvant settings with some trials suggesting that selected patients may avoid chemotherapy. Overall, current evidence supports the role of HRD as a promising biomarker in TNBC. However, further research is required to refine its clinical utility and to integrate HRD testing into personalized treatment strategies, especially in combination with emerging therapies such as immunotherapy.