PARP inhibitors are an exciting class of drugs that are revolutionizing targeted cancer treatment. By blocking the DNA repair pathways that cancer cells rely on, PARP inhibitors can selectively kill tumor cells without harming normal cells. However, not all patients respond equally well to these agents. Identifying reliable biomarkers that predict response has become a major focus of research to optimize the use of PARP inhibitors.

Homologous Recombination Deficiency and BRCA Mutations

It is well established that PARP Inhibitor Biomarkers are most effective in cancer types characterized by homologous recombination deficiency (HRD), a defect in the ability to accurately repair double-stranded DNA breaks. The clearest example of HRD is caused by mutations in BRCA1 and BRCA2 genes, which play a key role in the homologous recombination pathway. Clinical trials have shown exceptional responses to PARP inhibitors in breast, ovarian and prostate cancers with germline or somatic BRCA mutations, with objective response rates often exceeding 50%. As a result, BRCA mutation status is the current gold standard biomarker used to select patients most likely to benefit from PARP inhibitor therapy.

Beyond BRCA Mutations

However, HRD and PARP inhibitor sensitivity is not limited only to BRCA mutation carriers. Other genetic or epigenetic alterations can also impair the homologous recombination DNA repair pathway and confer PARP inhibitor sensitivity through a “BRCAness” phenotype. Areas of ongoing research include the roles of mutations in other HR DNA repair genes like ATM, PALB2, CHEK2 and RAD51C/D. Aberrant methylation silencing key HR genes like BRCA1 may also elicit a BRCA-deficient phenotype. Assays to comprehensively assess genome-wide loss of heterozygosity, large-scale state transitions and telomeric allelic imbalance are helping characterize the broader HRD phenotype beyond just BRCA mutations.

Tumor Mutational Burden

High tumor mutational burden (TMB), a measure of the number of mutations within the genome of a patient’s tumor, has emerged as another potential biomarker for PARP Inhibitor Biomarkers response. Cancers with elevated TMB may have defective DNA damage response and repair pathways rendering them reliant on error-prone alternative pathways like poly(ADP-ribose) polymerase activity. Initial studies reported a correlation between high TMB and clinical benefit from the PARP inhibitor olaparib in various advanced solid tumors. Ongoing research aims to establish standardized, clinically-validated TMB cutoffs to predict PARP inhibitor sensitivity. TMB may help identify additional biomarker-selected populations beyond just those with inherited BRCA mutations.

Circulating Biomarkers

While tumor tissue-based biomarkers offer direct assessment of genomic alterations driving cancer cell vulnerability, minimally-invasive circulating biomarkers hold promise for real-time patient monitoring and therapy guidance. Cell-free tumor DNA (ctDNA) analysis allows longitudinal profiling of mutational status and tumor evolution in blood samples, circumventing the need for repetitive tumor biopsies. Emerging evidence links higher levels of ctDNA shedding to superior PARP inhibitor response, supporting its potential use for early response monitoring. Similarly, extracellular vesicles like exosomes harboring DNA, RNA and protein are being explored as sources of non-invasive biomarkers. Multi-analyte panels incorporating genomic and epigenomic sequencing, transcriptomic profiling and proteins in circulation hold excitement as the next frontier of PARP inhibitor biomarkers.

Predictive Biomarkers in Clinical Trials

Rigorous clinical investigation in large randomized trials is still needed to validate many of the emerging predictive biomarkers discussed and establish their clinical utility. Trials like LODESTAR, PROFOUND and BRCA-NOVA are prospectively evaluating homology-directed repair gene alterations and their associations with PARP inhibitor benefit in breast, prostate and ovarian cancers respectively. The PAOLA-1 trial aims to determine the predictive value of BRCA, RAD51C/D alterations and genomic scarring in advanced ovarian cancer treated with niraparib maintenance. Comprehensive correlative biomarker analyses from these and future studies of PARP inhibitor combinations will be instrumental to refine patient selection and optimize personalized therapies guided by increasingly precise molecular profiling.

While germline or somatic BRCA1/2 alterations remain the gold standard predictor, expanding research into a broader landscape of HRD biomarkers, tumor mutational burden and circulating biomarkers holds promise to strengthen patient stratification for PARP inhibitor therapy. Ongoing investigation in well-designed clinical trials will be crucial to validate emerging biomarkers and fully realize the promise of precision oncology using PARP inhibitors. More sensitive and specific predictive signatures will facilitate matching the right drug to the right patient at the right time, advancing individualized cancer management.

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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it.