MADRID-Maintenance therapy with rucaparib can significantly improve progression-free survival (PFS) in patients with platinum-sensitive, recurrent ovarian cancer, according to a new study. The PARP inhibitor increased PFS by 77 percent in patients with BRCA-mutant recurrent ovarian cancer.
Most ovarian cancer presents as advanced disease and 80 percent of those patients will recur after first-line treatment. Patients often respond again to chemotherapy, particularly platinum-based chemotherapy, but they almost inevitably relapse again and eventually die of their disease. Maintenance treatments are needed to reduce recurrence in patients who have already relapsed, said lead investigator Jonathan Ledermann, BSc, MD, FRCP, Professor of Medical Oncology at the UCL Cancer Institute in London.
The PARP enzyme helps initiate the repair of DNA damage so that cells can continue to divide. DNA repair processes are inherently impaired in tumor cells with BRCA mutations. PARP inhibitors, such as rucaparib, block DNA repair and cells with BRCA mutations die.
"Rucaparib is a potent PARP inhibitor that has shown antitumor activity in patients with recurrent ovarian cancer whose tumor harbors BRCA mutations and wild-type BRCA with a high percentage of genomic loss of heterozygosity (LOH), a phenotypic marker of homologous recombination deficiency (HRD)," noted Ledermann.
Rucaparib is approved in the U.S. for the treatment of patients with deleterious BRCA mutations (germline or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapy regimens.
More than 20 percent of patients with ovarian cancer have BRCA mutations and are susceptible to PARP inhibitors. Some others with the disease are also susceptible, such as patients who respond to platinum-based chemotherapy and those with a high degree of genomic LOH.
ARIEL3 Study Results
At the ESMO 2017 Congress, Ledermann reported the results of the ARIEL3 clinical trial (Abstract LBA40_PR). This trial evaluated rucaparib versus placebo as maintenance treatment in 564 patients, average age 61.5 years, with recurrent platinum-sensitive ovarian cancer, including fallopian tube and primary peritoneal carcinomas. These patients with high-grade ovarian cancer had responded to platinum-based chemotherapy in the second- or third-line of treatment.
Eligible patients received two or more prior platinum-based therapies, had platinum-sensitive ovarian cancer, and had achieved a complete response or partial response to their most recent platinum. They were randomized to receive oral rucaparib maintenance therapy 600 mg twice daily (375 patients) or placebo (189 patients). The two patient arms were well-balanced, Ledermann noted.
The primary endpoint was PFS, which was measured sequentially in three groups if benefit was found in the previous group: 1) BRCA mutant; 2) BRCA mutant or BRCA wild-type with high LOH (together called HRD); 3) intention to treat (entire study population).
Rucaparib led to a statistically significant improvement in PFS in all three groups. PFS increased from 5.4 months to 16.6, 13.6, and 10.8 months in groups 1, 2, and 3, respectively, with hazard ratios of 0.23, 0.32, and 0.36, respectively.
"The improvement in PFS was greatest in the BRCA-mutated group, who had a 77 percent increase, but it was seen across three subgroups that were evaluated," said Ledermann.
In exploratory analyses, patients without BRCA mutations (wild-type) were divided into high LOH and low LOH groups. As expected, patients with high LOH had more improvement in PFS than those with low LOH, he said. But in both high and low LOH subgroups, rucaparib was statistically significantly better than placebo.
"We had hoped that the LOH test would distinguish responders from non-responders, but both high and low LOH groups benefitted. However, the magnitude of PFS benefit was greater in the BRCA wild-type/LOH high patients," said Ledermann.
Rucaparib was well-tolerated and just 13 percent of patients discontinued the drug due to side effects. The most common side effects were gastrointestinal (nausea and vomiting), asthenia, and anemia, which are consistent with previous phase II studies of the drug, he said.
Research Commentary
"Rucaparib maintenance treatment significantly improved PFS versus placebo in the nested BRCA-mutant and HRD cohorts and in the overall treatment population," Ledermann explained. "PFS was improved with rucaparib versus patients on placebo in patients with BRCA wild-type ovarian cancer, both low and high LOH."
Several patients with measurable residual disease at baseline had further reduction in tumor burden with rucaparib maintenance treatment, he noted.
"PARP inhibitors are the biggest development in ovarian cancer therapy since the introduction of platinum drugs in the late 1970s and early 1980s. Rucaparib is clearly an exemplary member of this exciting class of drugs that can be used to treat women with recurrent ovarian cancer in the maintenance setting," Ledermann added.
Andres Poveda, Head of the Gynaecological Cancer Clinic, Oncology Foundation Institute Valencia, Spain, and Chair of the Gynaecologic Cancer Intergroup (GCIG), commented: "ARIEL3 achieved a huge decrease in the risk of relapse with rucaparib. All of the patient subgroups benefitted, especially those with BRCA mutations, but also HRD patients.
"In Europe, the PARP inhibitor olaparib is licensed as maintenance therapy, but only for patients with germline BRCA mutations," he added. "We are awaiting a decision on niraparib, another PARP inhibitor. The addition of rucaparib would expand the population of patients receiving benefit from this type of drugs."
Poveda concluded: "Personalized medicine has arrived in high-grade serious ovarian cancer. Further studies are needed to identify predictive biomarkers of response to PARP inhibitors. Specifically, we need to know whether there are non-HRD factors that predict response."
Mark L. Fuerst is a contributing writer.