PARP inhibitors have emerged as an important class of targeted therapies for cancers with DNA repair deficiencies, most notably BRCA-mutated breast and ovarian cancers. However, biomarkers that can predict response to PARP inhibitors are still being refined to maximize their benefits. Here we explore some of the most promising PARP inhibitor biomarkers and how they may drive more personalized cancer treatment in the future.

Homologous Recombination Deficiency Scores

One of the main mechanisms of action of PARP inhibitors is exploiting cancers that have defects in homologous recombination (HR), the high-fidelity DNA repair pathway. Tumors with HR deficiencies are unable to properly repair DNA double-strand breaks and are selectively killed by PARP inhibition. Several assays have been developed to measure a tumor’s degree of HR deficiency, known as homologous recombination deficiency (HRD) scores.

One such assay is the myChoice HRD test from Myriad Genetics, which analyzes loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions in a tumor’s genome to generate an HRD score. Higher HRD scores are strongly predictive of response to PARP inhibitors, regardless of BRCA mutation status. Other HRD scoring tests look at specific HR genes signatures. In the future, standardized HRD scoring may allow physicians to select optimal PARP inhibitor candidates regardless of tumor type.

Going Beyond BRCA

It has become clear that BRCA1/2 mutations, while important biomarkers, do not tell the whole story when it comes to PARP inhibitor response. Many BRCA-wildtype cancers still benefit from PARP inhibitors, likely owing to alterations in other HR genes. Researchers are working to characterize a growing list of “BRCAness” genes that may expand PARP inhibitor indications when abnormal.

Some key BRCAness genes include ATM, ATR, FANCA, FANCM, PALB2, RAD51C/D and CHEK2. Prospective trials are underway using multi-gene panels to identify HR-deficient tumors most sensitive to PARP inhibitors. Characterizing the full spectrum of biological pathways driving HR deficiency, not just single genes, will be crucial to optimize PARP inhibitor matching.

Combination Strategies

PARP inhibitors show great potential not just as monotherapies but in combination regimens. Many studies are exploring their use together with chemotherapy drugs, I/O therapies like PD-1 inhibitors, and other targeted agents. The goal is synergistic antitumor effects at lower drug doses and broader applicability across tumor types.

One promising combination is PARP inhibitors with platinum-based chemotherapy. Platinum agents damage DNA through crosslinking, and preclinical models show this damage is enhanced by PARP inhibition. Ongoing trials are testing this double attack especially in BRCA-mutated and HRD+ tumors. PARP inhibitors are also being combined with immune checkpoint inhibitors to stimulate potent anticancer immune responses in the HR-deficient tumor microenvironment. Biomarkers to identify cancers most optimized for these multi-pronged approaches will help maximize treatment benefits.

Liquid Biopsies on the Horizon

As biomarker research continues advancing, liquid biopsies analyzing circulating tumor DNA (ctDNA) in blood samples show promise as a non-invasive alternative to tumor biopsy. ctDNA reflects the genomic makeup of a patient’s cancer in real time and can be repeatedly sampled through disease progression and treatment.

Several studies demonstrate high concordance between homologous recombination deficiency markers in ctDNA vs. tumor tissue biopsies. This indicates ctDNA may one day be used for HRD scoring and dynamic PARP Inhibitors Biomarkers matching as cancers evolve genomic instability over time. Liquid biopsies could allow continuous monitoring and individualized treatment adjustments without repeated invasive procedures – a major advantage as combinatorial approaches become standard.

Biomarker Discovery is Ongoing

While considerable progress has been made, ongoing research is still needed to fully characterize the predictive landscape for PARP inhibitor benefit. Long-term biobanking of tumor samples from clinical trials will allow applying cutting-edge genomic technologies like whole exome/genome sequencing to uncover new predictive markers. Correlating these genomic alterations to real-world outcomes will further precision oncology by guiding optimal PARP inhibitor candidate selection and dosing strategies.

As the first targeted therapies for DNA repair defective cancers, PARP inhibitors have blazed a trail. But to maximize their impact, biomarkers must continuously evolve step-in-step with new biological insights. The quest for predictive biomarkers will both personalize PARP inhibitor usage today and provide valuable lessons for developing biomarkers for the next generation of precision cancer drugs.

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