LOH Potential Rucaparib Biomarker In BRCA Wild-Type Ovarian Cancer

Genome-wide loss of heterozygosity could help select BRCA wild-type patients with relapsed, platinum-sensitive ovarian carcinoma who may benefit from poly(ADP-ribose) polymerase inhibition

medwireNews: Among patients with recurrent, platinum-sensitive, high-grade ovarian cancer lacking a BRCA mutation, those with high genomic loss of heterozygosity (LOH) are more likely to benefit from treatment with rucaparib than those with low LOH, research suggests.

Researcher Elizabeth Swisher, from the University of Washington in Seattle, USA, and team explain that poly(ADP-ribose) polymerase (PARP) inhibitors have shown activity in ovarian cancers with homologous recombination deficiency, which could be indicated by the presence of not only BRCA mutations, but also genome-wide LOH.

Patients with high or low LOH had a “similar” duration of median progression-free survival (PFS) after treatment with the oral PARP inhibitor rucaparib, at 5.7 and 5.2 months, respectively, but high versus low LOH was associated with a significant 38% reduced risk of progression or death, say the investigators.

Moreover, women with high LOH were significantly more likely to achieve a confirmed RECIST response than their counterparts with low LOH, at 29% and 10%, respectively, and the median duration of response was also significantly longer, at 10.8 versus 5.6 months.

“Our results add to the increasing body of evidence showing the potential of homologous recombination deficiency analysis to identify patients who will benefit from PARP inhibitor treatment”, the ARIEL2 researchers write in The Lancet Oncology.

They add that the findings “extend the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutant tumours.”

Writing in a linked commentary, Antonio González Martín, from the MD Anderson Cancer Center Madrid in Spain, says that the “trial constitutes a valuable effort in the challenge of identifying which patients with wild-type BRCA can benefit from PARP inhibition.”

But given that the differences between the LOH high and low subgroups “were not particularly clinically relevant”, he believes that an efficient assay producing clinically meaningful results is “still some way off”.

In part 1 of the phase II ARIEL2 trial, 204 patients with high-grade ovarian cancer that had recurred after at least one prior platinum-based regimen were given rucaparib 600 mg twice a day for continuous 28-day cycles until disease progression or discontinuation for another reason. The Foundation Medicine T5 next-generation sequencing assay was used to identify the percentage of genomic LOH in biopsy samples, with a cutoff of 14% or more to define high LOH.

Of 164 patients with wild-type BRCA, 82 had high genome-wide LOH, 70 had low LOH, while 12 could not be classified due to insufficient neoplastic nuclei in the specimen.

The trial also included 40 patients with a deleterious germline or somatic BRCA mutation, who also derived a benefit from rucaparib treatment. The median PFS was significantly longer and the objective response rate higher for these patients than for BRCA wild-type patients with low LOH, at 12.8 versus 5.2 months and 80% versus 10%, respectively.

The most common treatment-emergent adverse events of at least grade 3 in the ARIEL2 trial were anaemia or decreased haemoglobin levels (22%) and increases in alanine aminotransferase or aspartate aminotransferase levels (12%).

Thirty-nine percent of study participants needed a dose reduction, but only 9% discontinued as a result of toxicity. Three patients died during the course of the study, but none of the deaths were attributed to the study drug. 

References

Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol; Advance online publication 28 November 2016. doi: http://dx.doi.org/10.1016/S1470-2045(16)30559-9

González Martín A. Progress in PARP inhibitors beyond BRCA mutant recurrent ovarian cancer? Lancet Oncol; Advance online publication 28 November 2016. doi: http://dx.doi.org/10.1016/S1470-2045(16)30621-0

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