New PARP Drug 'Could Benefit Most Ovarian Cancer Patients'

Liam Davenport

October 08, 2016

COPENHAGEN — Patients with platinum-sensitive recurrent ovarian cancer showed significantly improved disease-free survival with niraparib (Tesaro), regardless of underlying mutation status, in the first phase 3 trial to be conducted with a poly(ADP)-ribose polymerase (PARP) inhibitor.

The results showed that progression-free survival (PFS) improved by 73% in patients with a BRCA mutation and by 55% in those without such mutations.

The new data were presented here today at the 2016 European Society for Medical Oncology (ESMO) Congress and simultaneously published in the New England Journal of Medicine.

These results follow those for olaparib (Lynparza, AstraZeneca), another PARP inhibitor, which as reported by Medscape Medical News, is approved in Europe as maintenance treatment for adults with relapsed platinum-sensitive ovarian cancer. However, labeling retricts the use of olaparib to patients with BRCA-mutated ovarian cancer, limiting its use to approximately 15% to 20% of the patient population.

In contrast, current findings the ENGOT-OV16/NOVA trial, performed in collaboration with the European Network of Gynaecological Oncology Trial (ENGOT) groups, indicate that, with niraparib effective across the board, the vast majority of ovarian cancer patients could benefit.

"This is a breakthrough for patients with ovarian cancer" said lead investigator Mansoor Mirza, MD, chief oncologist, department of oncology, Copenhagen University Hospital-Rigshospitalet, Denmark, in a press release.

Dr Mansoor Mirza

"We have never seen such large benefits in PFS in recurrent ovarian cancer. Niraparib significantly improved all endpoints across a broad patient population, representing 70% of all ovarian cancer patients. These landmark results could change the way we treat this disease," he added.

Speaking at an ESMO press conference, Dr Mirza suggested that it is time to move niraparib "up front" and use it "right after we have done the primary treatment, and that's what we're doing right now in the trials."

Andrés Poveda, MD, head of the gynecological cancer clinic, Oncology Foundation Institute, Valencia, Spain, who was not involved in the study, agreed, saying that the study "more than doubles the population of patients who benefit from a PARP inhibitor," adding that "personalized medicine has arrived in high-grade serious ovarian cancer."

Study Details

In the first phase 3 trial of a PARP inhibitor as maintenance therapy in patients with recurrent ovarian cancer after at least two platinum-based regimens, researchers recruited 553 patients and determined whether they had a germline BRCA mutation (gBRCAmut; n = 203) or not (non-gBRCAmut; n = 350).

The team then randomized patients within each cohort in a 2:1 ratio to niraparib 300 mg or placebo once daily, with treatment given until disease progression, unacceptable toxicity, death, withdrawal of consent, or loss to follow-up, whichever came first. Treatment could also be stopped for up to 28 days because of hematologic toxicity, after which it could be restarted at a lower dose.

Median PFS was significantly longer in the gBRCAmut group with niraparib vs placebo, at 21.0 vs 5.5 months (hazard ratio [HR], 0.27; P < .0001), respectively. A similar pattern was seen in the non-gBRCAmut group, at 9.3 vs 3.9 months (HR, 0.45; P < .0001).

Within the non-gBRCAmut group, researchers also used the novel myCHOICE homologous recombination deficiency (HRD) test (Myriad Genetics) to determine which patients had homologous recombination DNA repair deficiencies (n = 162) and analyzed the impact of niraparib vs placebo in the subgroup.

Niraparib was again associated with a significant improvement in PFS compared with placebo in the HRD patient subgroup, with a median PFS of 12.9 vs 3.8 months (HR, 0.38; P < .0001), respectively.

There were also significant improvements in chemotherapy-free interval and time to first subsequent treatment with niraparib over placebo (P < .0001 for both), while patient-reported outcomes were similar between groups.

The most common grade 3/4 adverse events were thrombocytopenia, anemia, and neutropenia, in 33.8%, 25.3% and 19.6% of intervention patients, respectively. All were managed with dose modification. There were no deaths.

"Significant Step Forward"

Study discussant Sandro Pignata, MD, PhD, director, Instituto Nazionale Tumori, IRCCS Fondazione Pascale, Napoli, Italy, described the findings as a "significant step forward in the treatment of ovarian cancer."

He said that the "main novelty" of the study compared to previous investigations with PARP inhibitors was that nongermline-mutation patients were included alongside HRD-positive individuals.

For Dr Pignata, niraparib achieved "extraordinary results" in patients with BRCA mutations "that modified the clinical history of these patients," while the patient subgroups experienced significant benefits. He said that, overall, he feels these results will change the treatment of ovarian cancer and that we are ready to "move beyond" BRCA mutation for determining therapeutic choices.

Nevertheless, Dr Pignata asked, "Who are these patients who are responding to niraparib?" He noted that all patients were selected for being highly sensitive to platinum, "which is the main clinical parameter for selecting PARP inhibitors," and questions remain as to why the different subgroups, including HRD-negative patients, responded to treatment.

He added the it is important to note there were a number of patients in the current study who remained on treatment at 18 months, which has also been seen in trials of olaparib. "So, we have to concluded that there are many exceptional responders" to PARP inhibitors, he said. However, the across-the-board responses among subgroups means it is currently not possible to determine who will be a long-term responder.

Dr Pignata concluded by saying that PARP inhibitors are "here to stay," although new biomarkers are clearly needed to identify HRD-negative and exceptional responders.

The study was funded by Tesaro. Several coauthors reported acting as consultants for Tesaro, and S. Agarwal is an employee of Tesaro. Disclosures for the coauthors are listed in the article.

European Society for Medical Oncology (ESMO) Congress. Abstract LBA3_PR. Presented October 8, 2016.

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