BRCA2 mutation

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

Furthermore, G73-mediated RAD51 degradation synergizes with the PARP inhibitor olaparib, inducing synthetic lethality and re-sensitizing olaparib-resistant cancers to PARP inhibition. This fully small-molecule-based strategy presents a compelling strategy to overcome resistance to PARP inhibitors, expanding their therapeutic potential beyond patients with HR-deficient tumors.

Although PARP inhibitor olaparib has been approved for metastatic CRPC patients bearing BRCA1/2 mutations, its application is confined to this specific patient subpopulation...Their synergistic effect was confirmed in ex vivo explants from human PCa specimens. Our findings demonstrated CDK9 as a master regulator of BRCAness and proposed targeting CDK9 as a potential strategy to sensitize CRPC patients without BRCA1/2 mutations to PARP inhibition.

These data demonstrate that targeting HRD yields promising outcomes in stage III, HER2-negative, HRD breast cancer and that intensified chemotherapy with autologous stem cell rescue does not provide any advantage over state-of-the-art chemotherapy plus olaparib.

Current clinically approved PARP inhibitors (Talazoparib and Olaparib) show outstanding therapeutic capabilities but suffer from severe side effects. These findings identify compound 1a as a promising lead, while compounds 1b and 1c remain viable candidates for further optimization. However, experimental validation is critical to confirm the predicted biological activity and safety profiles.

The apparent BRCT enrichment observed in earlier unfiltered analyses appears to be driven by VUSs rather than pathogenic variants, highlighting the methodological necessity of pathogenicity filtering for clinically actionable inference. These findings provide cohort-scale supportive evidence for emerging clinical guidelines that recommend broader BRCA1/2 testing across breast cancer subtypes.

The phase III KEYNOTE-B96 trial in platinum-resistant disease demonstrated a progression-free survival benefit in the intention-to-treat population and an overall survival benefit in tumors with programmed death ligand 1 (PD-L1) combined positive score ≥1 when pembrolizumab was paired with weekly paclitaxel with or without bevacizumab, underscoring the value of an immunomodulatory chemotherapy backbone in earlier lines. We explain why single-analyte biomarkers-PD-L1, tumor mutational burden, homologous recombination deficiency/BRCA1/2-have not reliably enriched benefit and outline a multidimensional approach integrating genomic scars (e.g., mutational signature 3), immune functional state (Immunoscore, CD8⁺ tumor-infiltrating lymphocyte density and CD8⁺: regulatory T-cell ratio), and spatial architecture (inflamed, excluded, desert phenotypes). This framework aims to move beyond the all-comer era toward context-informed precision immunotherapy in ovarian cancer.

This case highlights the importance of accurate diagnosis and optimal surgical and systemic management in ovarian carcinosarcoma. While maintenance therapy with Olaparib was used in an individualized, off-label setting despite negative BRCA and HRD testing, this approach should not be generalized. Further studies are needed to better define the role of targeted therapies in this rare and aggressive tumor subtype.

This case underscores the utility of combining CA125 and imaging for early PPC detection in STIC-positive BRCA2 carriers, particularly in older patients. Olaparib may also offer therapeutic benefit.

Among 121 patients, 30 (24.8%) had BRCA1, 88 (72.7%) had BRCA2, and three (2.5%) had dual mutations; 66.9% received first-line therapy, with ribociclib in 69.4% and palbociclib in 29.8%. In multivariable analysis, ECOG ≥ 1 (HR 1.85; p = 0.010) and fulvestrant-based therapy (HR 1.74; p = 0.041) predicted shorter PFS; fulvestrant also predicted worse OS (HR 2.39; p = 0.008). CDK4/6 inhibitor-based therapy shows meaningful activity in gBRCAm HR+/HER2- MBC; the numerically poorer outcomes observed in BRCA2 carriers are hypothesis-generating and warrant validation in larger cohorts.

As the first prospective real-world study of niraparib 1LMT in China, RENI-1 provides powerful complementary evidence to pivotal randomized controlled trials conducted in highly selective populations, further supporting niraparib as the first-line maintenance standard treatment.

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