Robert Coleman, MD
A dual-action PARP inhibitor has shown sufficient clinical activity to continue its investigation in women with recurrent BRCA-mutant ovarian cancer, preliminary results from an ongoing phase II trial showed.
Eight of 31 evaluable patients had partial responses to veliparib, which inhibits both PARP-1 and PARP-2. An additional 20 patients have not reached the follow-up period necessary to assess response, Robert Coleman, MD, reported at the 2013 Annual Meeting of the Society of Gynecologic Oncology.
Most of the 51 patients enrolled had minimal hematologic toxicity, whereas a majority had one or more types of nonhematologic adverse events, particularly nausea.
“Although early for overall assessment, veliparib, at this dose and schedule, is tolerable in this population,” said Coleman, professor of Gynecologic Oncology at the University of Texas MD Anderson Cancer Center in Houston. “The clinical activity in this phase II trial has met the minimal efficacy benchmark to be considered ‘of clinical interest.’”
“The overall response rate is unknown at this point, as too few patients have been on treatment long enough to assess response.”
Follow-up duration is insufficient to assess secondary outcomes, which include progression-free survival (PFS) and overall survival, he added.
Veliparib is one of almost a dozen PARP inhibitors in various stages of clinical evaluation. The agents are being tested in several types of solid tumors, including primary, recurrent, and platinum-sensitive/resistant ovarian cancer.
Veliparib is an oral drug that inhibits both isoforms of the targeted enzyme. Inhibition of PARP-1 disrupts the DNA-repair process that cancer cells require for continued development and progression. Inhibition of PARP-2 induces a toxic intracellular environment that enhances cell killing.
Substantial preclinical evidence has shown that targeting the DNA repair mechanism of BRCA
-mutant/ deficient tumors—which depends on poly(ADP-ribose) polymerase, or PARP— leads to specific killing of the cancer cells, said Coleman. PARP inhibitors are being evaluated as single therapy and in combination. To date, no phase II data on single-agent veliparib in BRCA-mutant ovarian cancer had been reported.
Coleman presented results from a two-stage phase II clinical trial involving patients with recurrent BRCA1/2
-mutant ovarian cancer, with a treatment history of as many as three prior regimens. Patients received 400 mg of veliparib twice daily until disease progression, unacceptable toxicity, or withdrawal from the study.
The primary endpoints were response rate (RECIST) and tolerability.
The trial protocol’s flexible two-stage design began with enrollment of 19 to 26 patients. If as many as two or three patients (depending on the number enrolled) had objective responses, the trial continued to the second phase with enrollment of as many as 51 patients. If as many as six or seven patients had objective responses in the two stages combined, the results met criteria for “clinically interesting” and warranted further investigation.
Of the 51 patients enrolled, 20 have not been evaluated for response. Of the remaining 31 patients, 25 remain on study and have completed as many as nine 28-day cycles of therapy. Coleman reported that 15 evaluable patients have completed at least three cycles.
The study population included 20 patients who had received two prior regimens and 17 who had three prior regimens. Few patients had been treated with radiation therapy (five) or immunotherapy (three), but only one patient had not undergone surgical resection.
Grade 1 hematologic adverse events consisted of neutropenia in 13 patients, thrombocytopenia in nine, and anemia in 17. Grade 2 hematologic toxicity consisted of three cases of neutropenia and five of anemia. No grade 3-5 hematologic toxicity was observed.
Nonhematologic toxicity occurred substantially more often, but was generally mild and manageable. Grade 1 adverse events included 18 cases of nausea, 20 cases of unspecified gastrointestinal (GI) problems, 19 cases of metabolic/nutrition events, 15 episodes of nervous system disturbances, and 11 cases of psychiatric disorders.
Nausea was the only grade 2 toxicity that occurred in as many as 10 patients, affecting 20. Two patients had grade 3 nausea and one each had grade 3 metabolic/ nutrition disorders and other GI disorders. A single case of grade 4 toxicity occurred (infection), and no patients developed grade 5 toxicity.
Investigators documented eight partial responses, and an additional 10 patients had not undergone the two required CT scan assessments to determine response status (including some patients with unconfirmed responses). An additional 27 patients had stable disease (some with unconfirmed responses), and six patients had progressive disease.
Additional response data will be reported as available, as will secondary-endpoint data, Coleman said.
Coleman R, Sill M, Aghajanian C, et al. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation - a Gynecologic Oncology Group study. Presented at: 2013 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 9-12, 2013; Los Angeles, CA. Abstract LBA5.