FDA Approved PARP Inhibitor Rucaparib For Maintainance Treatment for Recurrent Ovarian Cancer Boosting Need for Clinical NGS Testing

By Anthony M Magliocco MD

On April 6, 2018, the Food and Drug Administration approved rucaparib (Rubraca®, Clovis Oncology Inc.), a poly ADP-ribose polymerase (PARP) inhibitor, for the maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.      

Approval was based on ARIEL3 (NCT01968213), a randomized, double-blind, placebo-controlled trial in 561 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with at least two prior treatments of platinum-based chemotherapy and were in complete or partial response to the most recent platinum-based chemotherapy. Patients were randomized (2:1) to rucaparib 600 mg orally twice daily (n=372) or placebo (n=189) and were treated until disease progression or unacceptable toxicity. 

Tumor tissue samples were examined with a next-generation sequencing assay to determine whether DNA contained a deleterious somatic or germline BRCA mutation (tBRCA). This test was also used to determine the percentage of genomic loss of heterozygosity (LOH). Positive homologous recombination deficiency (HRD) status was defined as tBRCA-positive and/or LOH high. Three patient outcomes analyses were performed on the following groups: all patients, HRD subgroup, and tBRCA subgroup.

NGS ASSAY WAS REQUIRED TO IDENTIFY BRCA MUTATIONS

 

ARIEL3 demonstrated a statistically significant improvement in estimated median progression-free survival (PFS) assessed by investigator for patients randomized to rucaparib compared with placebo in all patients (median PFS 10.8 vs. 5.4 months, HR 0.36; 95% CI:0.30, 0.45; p<0.0001), in the HRD subgroup (median PFS 13.6 vs. 5.4 months, HR 0.32; 95% CI: 0.24, 0.42; p<0.0001), and in the tBRCA subgroup (median PFS 16.6 vs. 5.4 months, HR 0.23; 95% CI: 0.16, 0.34; p <0.0001).

 

The FDA also concurrently approved the complementary diagnostic test, FoundationFocusTM CDx BRCA LOH, for tumor samples to determine HRD status. 

In ARIEL3, the most common adverse reactions in at least 20% of patients treated with rucaparib included nausea, fatigue (including asthenia), abdominal pain/distension, rash, dysgeusia, anemia, ALT/AST elevation, constipation, vomiting, diarrhea, thrombocytopenia, nasopharyngitis/URI, stomatitis, decreased appetite, and neutropenia. Myelodysplastic syndrome and/or acute myeloid leukemia occurred in 7 of 372 (1.9%) patients treated with rucaparib and in 1 of 189 (0.5%) patients assigned to placebo. Discontinuation due to adverse reactions occurred in 15% of patients receiving rucaparib and 2% of those assigned to placebo. 

The recommended rucaparib dose is 600 mg (two 300 mg tablets) taken orally twice daily with or without food.

FDA granted this application priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:

 

This approval is another example of the exploding need to broad access to next generation sequencing in routine clinical care of cancer patients forming the foundational basis of personalized oncology

” This most recent approval of yet another therapeutic advance that is reliant on NGS for patient selection further increases the urgency for access to routine NGS for all cancer patients”  – Anthony M Magliocco MD

The Moffitt Morsani Laboratories have developed and launched a new NGS assay ‘Moffitt STAR(TM)” that covers the key actionable target genes including BRCA1 and BRCA2

Moffitt STAR NGS panel covers the key mutations

PierianDx Customer, Moffitt Cancer Center, Launches Clinical NGS Assay, STAR

VISIT MOFFITT CANCER CENTER WEBSITE

http://www.moffitt.org

 

New Mechanism Involving NFkappaB Drives Metastasis in Cancer with Chromosomal Instability

By Anthony M Magliocco MD

An interesting and important new study recently published in Nature gives new insights into possible targetable molecular mechanism linking chromosomal instability observed in some cancers and progession and metastasis.

https://www.nature.com/articles/nature25432

A subset of cancers develop chromosomal instability via disjunction errors during mitosis. This can lead to highly aneuploid and abnormal karyotypes more prevalent in certain cancers than other. For example, ovarian cancer is notorious for developing a  disrupted and unstable karyotype.

Metastatic Cancer

It appears that chromosomal instability in itself does not promote metastasis, however, in an intriguing observation it was noted that tumors with chromosomal instability also developed micronuclei when under mechanical stress.

These micronuclei are more prone to cytoplasmic rupture. Free DNA in the cytoplasm triggers a non-canonical NFkappaB cascade which may lead to mesenchymal transformation and a propensity to metastasis.

Interestingly cancers with high aneuploidy do not generally develop a high mutational burden such as cancers like melanoma. Nor do they tend to have targetable driver mutations.

“Cytosolic DNA from micronuclear rupture appears to trigger non-cannonical NFKappaB signaling which could lead to tumor metastasis”

 

DNA in the cytoplasm triggers NFKappaB as part of a host response to viral infection, but cancer may subvert this mechanism. In addition,  NFkappaB non-cannonical activation by cytosolic DNA from ruptured micronuclei may lead to a variety of effects immune activation which could assist with tumor metastasis.

These new insights into the consequences of chromosomal instability create opportunities for developing new therapeutic strategies for these types of cancer that lack specific driver mutations and significant neoantigen loads