Genomic LOH Signature Predicts PARP Inhibitor Response

Genomic LOH Signature Predicts PARP Inhibitor Response

The Clearity Foundation

Evan Friend, MD

Preliminary results from a Phase 2 clinical trial (“ARIEL-2”) testing the PARP inhibitor rucaparib in ovarian cancer patients with platinum-sensitive recurrent cancer were presented at the recent EORTC-NCI-AACR conference.  Much excitement has been generated from the interim analysis of this trial, since for the first time, a biomarker (“biological indicator”) consisting of an actual “signature” event identified from an individual patient’s tumor was found to correlate with favorable responses (to see the interim results, click here). Importantly, in addition to BRCA1/2 mutant patients, for whom PARP inhibitors have previously shown clinical effectiveness, the women without BRCA mutations whose cancer was positive for the identified genomic signature also derived significant benefit from rucaparib.

The signature event is described as “loss of heterozygosity (LOH)” within the genome.  This refers to the loss of an entire chromosomal region on one copy of the double-stranded DNA genome and is a sign of DNA damage that has occurred in the tumor.  As expected, high levels of this type of damage were found in the tumors of patients who have BRCA mutations.  Moreover, this genomic LOH signature seems to match the state of “BRCAness”, which describes BRCA mutation-negative women whose tumors behave as though there was a BRCA mutation, and have responded to PARP inhibitors in previous trials.  Now, for the first time, we have preliminary favorable results from a clinical trial that yields not only a specific biomarker protein or gene, but in this case, a specific molecular DNA “signature” which will hopefully allow clinicians to identify those patients who would be expected to derive the maximum benefit from the addition of PARP inhibitors to chemotherapeutic regimens, both in the relapse and maintenance settings.

An “ARIEL-3” (maintenance setting, platinum-sensitive patients) Phase 3 clinical trial is currently underway and will evaluate the effects of the PARP inhibitor rucaparib in women whose cancers have been tested for the presence of BRCA mutations as well as for this genomic LOH signature.  Thus, that study will prospectively show whether this signature is a significant predictor of rucaparib benefit.  Stay tuned!

The information included in this newsletter is for educational purposes only. It is not intended nor implied that this information be a substitute for professional medical advice. You should always consult your healthcare provider to determine the appropriateness of the information for your own situation.

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