Rucaparib Leads to Frequent Durable Remissions in BRCA-Mutated Relapsed Ovarian Cancer


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Rucaparib (Rubraca) led to frequent durable remissions among patients with relapsed high-grade ovarian cancer with BRCA mutations, regardless of whether the mutations were germline or somatic, according to the results of the ARIEL2 trial presented at the 2017 Society of Gynecologic Oncology Annual Meeting.1 Antitumor activity was associated with platinum sensitivity and inversely correlated with the number of prior chemotherapy regimens.


Objective response rates with rucaparib in primary mutated ovarian cancer, both somatic and germline mutations, were extraordinary, ranging between 52% and 86%, depending on the number of prior therapies.
— Gottfried E. Konecny, MD

Patients with platinum-sensitive disease appeared to benefit most from the PARP (poly ADP-ribose polymerase) inhibitor, according to Gottfried E. Konecny, MD, of the University of California, Los Angeles. Treatment with rucaparib produced responses in 70% of patients with platinum-sensitive ovarian cancer, with median progression-free survival of almost 13 months. Response rates and median progression-free survival were less robust for patients who had at least three prior lines of therapy and for those who were platinum-resistant or platinum-refractory.

“I think the objective response rates with rucaparib in BRCA-mutated ovarian cancer, with either a somatic or germline mutation, were extraordinary, ranging between 52% and 86%, depending on the number of prior therapies,” Dr. Konecny commented, referring to platinum-sensitive patients whose immediate prior treatment included a platinum.

ARIEL2 Details

Rucaparib is approved in the United States as monotherapy for the treatment of patients with advanced ovarian cancer with deleterious BRCA mutations (germline or somatic) after two or more lines of chemotherapy. This approval was supported by integrated data from Study 10 and ARIEL2, he said.

ARIEL2, which included 493 patients, assessed response and progression-free survival in patients with ovarian, primary peritoneal, or fallopian tube cancer, regardless of BRCA-muatation status. It also examined the effect of platinum sensitivity and the number of prior lines of chemotherapy on outcomes.

Part 1 of the trial included 206 patients who had received at least 1 prior platinum-based regimen and were considered platinum-sensitive (ie, disease progression occurred at least 6 months after treatment). Part 2 included 287 patients treated with 3 or 4 prior chemotherapy regimens. They could be platinum-sensitive, platinum-resistant (ie, disease progression < 6 months after last platinum), or platinum-refractory (best response was progressive disease on last platinum, during or up to 2 months after treatment).

The current analysis focused on 134 patients with germline or somatic BRCA mutations, including 41 from Part 1 and 93 from Part 2 of ARIEL2. The majority of mutations (58%) were germline; 17% were somatic; and 25% were of uncertain origin. Two-thirds of the mutations were BRCA1.

Outcomes by Subgroup

The objective response rate was greatest in platinum-sensitive patients, ranging from 52% to 86%, depending on the number of prior therapies. The same was true for progression-free survival. Median progression-free survival was 12.7 months in platinum-sensitive patients, 7.3 months in platinum-resistant patients, and 5.0 months in patients considered refractory to platinum, Dr. Konecny reported.

Rucaparib in Relapsed Ovarian Cancer

  • The PARP inhibitor rucaparib led to responses in 70% of patients
    with platinum-sensitive relapsed ovarian cancer with BRCA mutations, and median progression-free survival of almost 13 months, in the
    ARIEL2 trial.
  • Response rates ranged from 52% to 86%, depending on the number of prior therapies, in platinum-sensitive patients whose last treatment included a platinum agent.
  • Median progression-free survival was 12.7 months in platinum-sensitive patients, 7.3 months in platinum-resistant patients, and 5.0 months in patients considered refractory to platinum.

By degree of platinum sensitivity, patients whose progression-free interval was 18 months or longer had a median progression-free survival of 25.1 months. Median progression-free survival was 16.9 months for patients whose last remission lasted at least 12 months and 12.7 months for patients whose remission lasted at least 6 months.

By location of mutation, there was no difference in median progression-free survival and response rates between somatic and germline mutations. Median progression-free survival was approximately 13 months in each, and response rates were approximately 75%. Outcomes according to BRCA1 vs BRCA2 were also comparable.

Secondary somatic BRCA mutations were detected in 8 of 55 patients with platinum-resistant or platinum-refractory disease, in screening tumor biopsies or circulating tumor DNA.

The most common treatment-emergent adverse events included nausea (78%), fatigue (78%), vomiting (49%), and anemia (48%). The most common grade 3/4 toxicities were anemia, liver enzyme elevations, and fatigue.

“These are very promising data and are currently being validated in an ongoing prospective trial,” Dr. Konecny said.

Tissue Analysis

Elizabeth Swisher, MD

Elizabeth Swisher, MD

Elizabeth Swisher, MD, of the University of Washington, Seattle, reported these results from tissue analysis in ARIEL22:

  • Routine sequencing of high-grade ovarian cancer would identify at least 10% to 15% of patients with somatic mutations and 20% with germline mutations likely to respond to PARP inhibition.
  • BRCA1 and RAD51C methylation in ovarian tumors is associated with a high loss of heterozygosity and sensitivity to rucaparib.
  • Loss of BRCA1 methylation is common after exposure to platinum chemotherapy, even in “platinum-sensitive” patients.
  • CDK12 mutations may confer PARP inhibitor sensitivity as well as mutations in other core homologous recombination genes. ■

Disclosure: Dr. Konecny has received honoraria and research funding as well as has participated in the speakers bureau for AstraZeneca, Clovis Oncology, Amgen, Merck, and Novartis. Dr. Swisher reported no potential conflicts of interest.

References

1. Konecny GE, Oza AM Tinker AV, et al: Rucaparib in patients with elapsed, primary platinum-sensitive high-grade ovarian carcinoma with germline or somatic BRCA mutations: Integrated summary of efficacy and safety from the phase 2 study ­ARIEL2. 2017 Society of Gynecologic ­Cancer Annual Meeting. Abstract 1. Presented March 12, 2017.

2. Swisher EM, Harrell MI, Lin K, et al: BRCA1 and RAD51C promoter hypermethylation confer sensitivity to the PARP inhibitor rucaparib in patients with relapsed, platinum-sensitive ovarian carcinoma in ARIEL2 Part 1. 2017 Society of Gynecologic Oncology Annual Meeting. Abstract 7. Presented March 12, 2017.


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— Jonathan Ledermann, MD

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