CHICAGO – Olaparib, the novel PARP inhibitor that came up short of a survival advantage in a much-watched trial in ovarian cancer, is again showing positive results in that disease.
Olaparib was effective and well tolerated as an adjunctive targeted therapy in women with platinum-sensitive advanced serous ovarian cancer, regardless of BRCA mutational status, according to new results from a different randomized, open-label phase II trial.
Among the 162 women studied, those treated with olaparib – an oral investigational inhibitor of PARP, or poly(ADP-ribose) polymerase – along with chemotherapy and also as maintenance therapy had a nearly one-half reduction in the risk of progression or death relative to their counterparts treated with chemotherapy alone and no maintenance therapy.
The absolute difference in the risk of events was about 3 months, investigators reported at the annual meeting of the American Society of Clinical Oncology.
"There is an active biomarker analysis program to analyze tumor tissue, and the analysis of samples from this study will be combined with the samples from [a monotherapy maintenance study] to look at potential predictive biomarkers for olaparib efficacy," noted first author Dr. Amit M. Oza of Princess Margaret Hospital in Toronto.
"Olaparib clinical development continues, and the immediate aims are to determine the optimal patient population and to find an acceptable tablet dose and schedule for long-term treatment, to enable the next generation of clinical studies," he added.
Dr. Michael V. Seiden of the Fox Chase Cancer Center in Philadelphia cited the earlier study of olaparib maintenance, which showed improved progression-free survival but, at least as of an interim analysis, not overall survival in his invited discussion of the current study (N. Engl. J. Med. 2012;366:1382-92).
"If we as a community are going to bend the survival curves of ovarian cancer upward, we are going to need to find a therapeutic strategy that works in advanced serous carcinoma," he said. Although the study was "positive ... perhaps a bit provocatively, I am going to argue that I suspect this study will ultimately be negative – negative not in that it didn’t meet its therapeutic end point, but in that it will fail to bend the ovarian cancer survival curve upward."
Serous ovarian cancers have extremely diverse genomic aberrations, so it is unlikely that there are large groups of patients with similar tumors, according to Dr. Seiden.
"The genomics of serous carcinoma argue against phase III studies at least of what I would argue are molecularly targeted agents. Bringing new drugs to our patients will require new strategies in clinical trial design, new strategies in genomic stratification, and new strategies in FDA approval," he maintained.
The women studied in the trial were 60 years old on average, Dr. Oza reported at the meeting. In 80% of cases, the cancer’s status regarding mutations of the BRCA genes (which have been associated with greater PARP inhibitor efficacy in some cancers) was unknown. The majority of women had received only a single platinum-containing regimen.
The investigators assigned the women evenly to chemotherapy (paclitaxel plus carboplatin) with concurrent olaparib, followed by olaparib maintenance, or to chemotherapy alone followed by no maintenance therapy. The carboplatin dose was one-third lower in the group given olaparib. "In this study, we used the capsule formulation of olaparib," he noted.
Study results showed that median progression-free survival was 12.2 months with olaparib and 9.6 months without it (hazard ratio, 0.51; P = .001).
"The curves begin to separate at 6 months and after that. So there was no separation of the two curves during the concurrent portion of the treatment," Dr. Oza pointed out.
"There were no specific subgroups that did not seem to benefit from the addition of olaparib," he continued, although benefit was somewhat greater in women who had a progression-free interval exceeding 12 months before the trial as compared with a shorter duration.
Immature data for overall survival showed a rate of about 15% with olaparib and 14% without it. There were no significant differences between the groups in terms of response rate whether assessed with RECIST criteria (64% vs. 58%) or cancer antigen 125 (CA-125) levels (86% vs. 74%).
Women known to have BRCA mutations appeared to be scattered evenly throughout a waterfall plot showing the degree of response (or lack thereof), Dr. Oza noted.
The combination regimen "was well tolerated and deliverable," with similar rates of dose modifications and completion of chemotherapy," he said. During the concurrent phase of treatment, "the rates of grade 3 or worse neutropenia and thrombocytopenia are not dramatically different between the two arms, which is reassuring."