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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2014 Clinical Advances in Ovarian Cancer

2014 Clinical Advances in Ovarian Cancer

The Clearity Foundation

Cory Bentley, PhD

What has happened to the promising drugs that we have described in Clearity Survivor newsletters since 2010? Plenty. One has succeeded all the way to approval by the FDA. Several have shown anti-cancer activity in patients and continue to advance in clinical trials. Alas, some have failed. This article will highlight some of the most important developments in ovarian cancer treatment this year.

For the first time in 15 years, the FDA approved a new drug for patients who have platinum resistant disease. That drug is Avastin, which is anti-angiogenic; it works by interfering with new blood vessel formation – a key way for tumors to get nutrients as they grow. The phase III trial of Avastin, coined AURELIA, showed that the addition of Avastin improved both PFS (progression free survival) and ORR (overall response rate) compared to treatment with chemotherapy alone. (See the results for this trial and other trials testing anti-angiogenic treatments by clicking here).  Progression free survival (PFS) is the time from start of treatment until the tumor starts to grow. Overall response rate (ORR) is the percent of patients that show a partial response to treatment (some tumor shrinkage) or complete response (tumor no longer detectable). In this trial, Avastin was paired with a chemotherapy – Topotecan, Doxil, or Paclitaxel. Each pairing with Avastin led to an increased PFS of about two-fold compared to chemotherapy alone. A tumor blueprint can help guide the selection of one of these chemotherapeutic agents. In the future, there may also be a test that can predict if patients will respond to Avastin. At this year’s annual American Society of Clinical Oncology (ASCO) conference, researchers from Scotland reported that they had identified a tumor signature of Avastin response and studies to confirm those results are underway.

Another big story for ovarian cancer in 2014 relates to olaparib (Lynparza), a member of a class of drugs known as PARP inhibitors. Based on the review by European Medicines Agency in October, the European Union is expected to approve olaparib for the maintenance treatment of BRCA-mutated platinum sensitive relapsed ovarian cancer. Although the FDA chose not to approve this drug for use in the maintenance setting US based on the data from the phase II trial (they often wait for more rigorously performed phase III studies before approving a new drug), there is still optimism that PARP inhibitors will be therapeutic options in the US in the near future. The clinical trial results available for PARP inhibitors indicate that these drugs will be useful to treat patients with existing disease as well for those who are in remission. There are currently at least 20 ongoing clinical trials of PARP inhibitors either by themselves or combined with other drugs. Peruse them all by selecting PARP1/2 in the Molecular Target menu on the Clearity Foundation website.

Mutation in the BRCA1 or BRCA2 genes has been important in identifying patients that will respond to PARP inhibitors, but clinical trial evidence suggests that some patients without BRCA mutations may also respond. Now, Foundation Medicine has presented new data at a Symposium on Molecular Targets and Cancer Therapeutics in Barcelona (EORTC-NCI-AACR) molecularly identifying patients without BRCA mutations that are more likely to respond to the PARP inhibitor rucaparib. This molecular test may become a so-called companion diagnostic for rucaparib. Data from the PARP inhibitor, niraparib is also undergoing analysis for response predictors by Myraid Genetics using their companion diagnostic test that identifies tumors with deficiency in homologous recombination, something used by cells to repair harmful breaks in DNA. Clearity patients will recognize that the future availability of these types of tests that can add further detail to her tumor blueprint and provide important information for her treatment decisions. Positive trial data from PARP inhibitors along with the means to molecularly determine those women most likely to respond to them, sets the stage for this class of drugs to become an important option for ovarian cancer patients in the future.
The recent approval of Avastin and substantial progress in the clinical development of PARP inhibitors mark real progress being made against ovarian cancer in a field where progress has been so difficult. Clearity will continue to report on the development and approval of drugs that make a meaningful difference and offer true hope in our fight against ovarian cancer.
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.

Gene Expression Signature May Predict Avastin Benefit

Gene Expression Signature May Predict Avastin Benefit

The Clearity Foundation

Deb Zajchowski, PhD

 

The search for a biomarker to predict response to the angiogenesis inhibitor, bevacizumab (aka Avastin), may be nearing a successful conclusion.  Researchers at Edinburgh Cancer Research Center in Scotland reported that they may have discovered such a predictor for ovarian cancer patients treated with Avastin. They presented their findings at the June ASCO meeting and showed that this predictor is not a single gene or protein, but a “signature” that combines information from 63 genes.  The information is derived from molecules in the cell called messenger RNAs (mRNA), which act as communicators between the DNA blueprint in the cell nucleus and the cellular protein-making factory by giving instructions for the type of proteins that are to be made.  The investigators used tumor samples collected during a previous Avastin clinical trial (ICON7) in newly diagnosed patients who had surgery followed by standard platinum-based chemotherapy with or without Avastin.   They measured mRNA for these 63 genes in the tumors and designated them as “pro-angiogenic” or “immune”-like.   Those patients with “immune-like” tumors lived longer than those with “pro-angiogenic” tumors, suggesting that this signature might also be a prognostic marker.  Importantly, those women with “immune-like” tumors did not benefit when they were given Avastin as first-line treatment and for maintenance.  These results must be confirmed in additional studies and still need to be evaluated for recurrent ovarian cancer patients who receive Avastin-usually in combination with other chemotherapies.  But, the current data suggest that there may soon be a molecular test that will help patients and their doctors make informed decisions regarding the use of Avastin based on their tumor molecular profile in addition to the clinical factors, including cardiovascular issues or intestinal involvement of the cancer.

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.