Poly (ADP-ribose) polymerase (PARP) inhibitors are an important class of anticancer drugs used for the treatment of various cancers. These drugs work by blocking the action of PARP enzymes that are involved in DNA repair. Cancers with defects in homologous recombination repair (HRR) are particularly sensitive to PARP inhibitors. Identification of suitable biomarkers can help optimize the clinical use of PARP inhibitors and improve patient outcomes.
BRCA Mutations
The most important predictive biomarker for response to PARP inhibitors is mutations in BRCA1 and BRCA2 genes. BRCA1 and BRCA2 play a key role in HRR and cancers with mutations in these genes, referred to as BRCA-mutated or BRCAm cancers, show exceptional sensitivity to PARP inhibitors. Initial studies with the PARP inhibitor olaparib demonstrated unprecedented response rates of around 60% in BRCAm ovarian and breast cancers. FDA has approved olaparib as monotherapy for treatment of BRCAm advanced ovarian and metastatic breast cancers. Other PARP inhibitors like rucaparib and niraparib have also received approvals as monotherapy for BRCAm ovarian cancers. Detection of germline or somatic BRCA mutations helps identify patients most likely to benefit from PARP inhibitor therapy.
Homologous Recombination Deficiency
While BRCA mutations are the best established predictive biomarker, not all HRR-deficient cancers harbor BRCA mutations. Tumors can exhibit HRR deficiency through other genetic or epigenetic mechanisms as well. Assessing HRR deficiency directly through functional assays or indirectly through molecular profiles has emerged as a promising biomarker approach. Functional assays measuring loss of HRR capacity through inhibition of RAD51 foci formation or increased sensitivity to DNA crosslinking agents can identify HRR-deficient cancers independent of BRCA status. Molecular profiles measuring expression of HRR and cell cycle checkpoint genes have also shown correlation with response to PARP inhibitors. Ongoing clinical studies are evaluating HRD scores derived from tumor gene expression as predictive biomarkers. HRR deficiency, regardless of the underlying cause, remains the strongest predictive factor for PARP inhibitor sensitivity.
Genomic Scar
Genomic scars left behind by defective HRR in BRCAm and other HRD tumors constitute another pharmacodynamic biomarker of response to PARP inhibitors. PARP inhibition leads to trapping of PARP1 and PARP2 at sites of DNA damage in HRR-deficient cells resulting in replication fork collapse and formation of DNA double-strand breaks. This triggers characteristic patterns of mutational signatures known as genomic scars. Analysis of mutational signatures in pre-treatment and on-treatment tumors can detect enrichment of genomic scar signatures reflecting trapping of PARP and synthetically lethal interaction. Quantifying genomic scar formation provides a confirmation of on-target engagement of PARP inhibitors and HRR deficiency in tumor.
Tumor Mutational Burden
High tumor mutational burden (TMB) has emerged as a potential predictive biomarker independent of HRR or BRCA status. TMB acts as a surrogate for elevated neoantigen load and endogenous DNA damage which resembles an intrinsic form of HRR deficiency. Studies have shown PARP inhibitors to be active even in HRR-proficient tumors with ultra-high TMB. Ongoing trials are exploring TMB as a potential selection criterion to expand the utility of PARP Inhibitors Biomarkers to broader patient populations beyond just BRCA-mutated and HRD subgroups. Quantification of TMB through advanced genomic profiling techniques provides an agnostic biomarker approach to identify PARP inhibitor sensitive tumors.
Immunogenic Cell Death
Another possible predictive mechanism is through induction of immunogenic cell death by PARP inhibitors. PARP inhibition triggers release of damage-associated molecular patterns (DAMPs) and tumor antigens which trigger anti-tumor immune responses. Pre-clinical studies demonstrate PARP inhibitors to enhance immunogenicity and combination with immune checkpoint inhibitors to produce synergistic antitumor effects. Ongoing clinical trials are evaluating immune-related biomarkers like PD-L1 expression and tumor-infiltrating lymphocytes as potential biomarkers of response. Combining PARP inhibitors with immunotherapy also holds promise to expand their clinical benefits beyond HRR-deficient genomic subgroups.
Identification and validation of suitable predictive and pharmacodynamic biomarkers play a crucial role in optimizing clinical outcomes with PARP inhibitors. While BRCA mutations remain the gold standard predictive biomarker, expanding the approach to assess HRR deficiency independent of BRCA status through functional and molecular methods holds potential. Genomic scarring, TMB and immune biomarkers provide complementary approaches to select responsive patient subgroups in a biomarker-agnostic manner. Comprehensive biomarker profiling holds the key to maximize benefits of this important class of targeted therapies.
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The Global PARP Inhibitor Biomarkers market held USD 465.6 million in 2020 and is to grow with a CAGR of 24.2% from 2020-2030.
It consists of a group of 17 enzymes combining several (poly) ADP-ribose units in a chain and transferring them into the target proteins.
It is believed that PARP inhibitors are trapped in single-strand DNA pauses that lead to dual-strand DNA pausing when replication of the DNA is attempted.
Double-stranded DNA breaks would normally be re-mediated by the HRR process, an advanced process that includes several proteins, particularly BRCA1 and BRCA2, which are also known as PARP inhibitors biomarkersMarket Dynamics and Factors:Download Research Sample with Industry Insights @ https://www.trendsmarketresearch.com/report/sample/13663The main drivers for PARP inhibitors biomarkers market growth are the increasing prevalence of cancer worldwide.
In total, around 1 in 6 deaths occur because of ca, according to the same source.Increasing breast and ovarian cancer incidences are also expected to lead to PARP inhibitors biomarkers market growth over the projected period.
Breast cancer was among the 2nd largest total number of cancer cases worldwide, for example according to a 2018 report by the World Cancer Research Fund, which in 2018 accounted for 2,088,849 new cases.
