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Dr. Plummer noted that it is not yet known how much PARP has to be inhibited to achieve therapeutic activity.

The possibilities for PARP(PARP inhibitors are a group of pharmacological inhibitors of the enzyme Poly ADP ribose polymerase (PARP)) inhibitors are exciting, but the question remains whether enough has been learned about these DNA repair pathways to manipulate them for clinical benefit.

PARP inhibitors that are far enough along in development to have names (e.g., olaparib, iniparib, and veliparib) have shown promise, but the variability in responses suggests that the mechanism of activity of these compounds is not yet fully understood. They are being studied in a wide range of tumors including breast, ovarian, pancreatic, and prostate.
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Olaparib Shows Promise as Maintenance Therapy in Relapsed Serous Ovarian Cancer

Evidence supporting the benefit of olaparib in advanced ovarian cancer continues to grow.

A phase II study showed that this orally active PARP inhibitor markedly prolonged progression-free survival (PFS) when used as maintenance therapy in patients with high-grade relapsed serous ovarian cancer who had responded to previous treatment with platinum-based chemotherapy.


?Standard practice is to observe such patients after chemotherapy until further disease progression. There is a great need to find treatments that might delay the reappearance of disease,? explained Jonathan Ledermann, MD, of University College London, United Kingdom, who explained the rationale for the study and presented the findings during Saturday?s Gynecologic Cancer Oral Abstract Session (Abstract 5003).

Prior studies established the benefit of olaparib induction therapy in patients with recurrent advanced ovarian cancer. However, the current study is the first to demonstrate a substantial clinical benefit following maintenance therapy with olaparib ? or any PARP inhibitor ? in platinum-sensitive relapsed serous ovarian cancer.

The randomized, double-blind, placebocontrolled study enrolled 265 patients from 82 sites in 16 countries. Eligible patients had received at least two previous platinum- based chemotherapy regimens.

After ensuring that the partial or complete response achieved during the last platinumcontaining regimen was sustained, patients were randomly assigned to receive 400 mg of oral olaparib twice daily or placebo until evidence of disease progression.

Dr. Ledermann reported that olaparib improved PFS ? the primary study endpoint ? by 3.6 months following the completion of chemotherapy as compared with placebo, translating to a 65% reduced risk of progression (Fig. 1).

Importantly, in a preplanned subgroup analysis, the PFS benefit associated with olaparib was not restricted to patients who were BRCA-mutation positive ? a status thought to enhance responsiveness to PARP inhibition. In fact, all subgroups, including those broken out by BRCA-mutation status, age, race or Jewish ethnicity, prior response to the last platinum regimen, and time to disease progression on the penultimate platinum regimen, showed a substantial PFS benefit in favor of olaparib.

The time to progression according to either CA-125 concentration or RECIST was also significantly longer with olaparib compared with placebo (median: 8.3 vs. 3.7 months; hazard ratio: 0.35; 95% CI [0.25, 0.47]; p < 0.00001). Overall survival data are not yet mature, as only 19 deaths were observed at the time of analysis (nine deaths in the olaparib group; 10 deaths in the placebo group).

Olaparib was generally well tolerated, with a safety profile consistent with that seen in previous studies. The most common adverse events associated with olaparib compared with placebo included nausea (68% vs. 35%), fatigue (49% vs. 37%), and vomiting (31% vs. 14%); the majority of these events were mild or moderate in severity.

The most common grade 3/4 events were fatigue (7%) and anemia (5%). Very few patients discontinued olaparib because of adverse events (three patients; 2%).

Stanley B. Kaye, MD, of the Royal Marsden Hospital, United Kingdom, said in a discussion of Dr. Lederman?s presentation, ?What we know now is that single-agent olaparib does have significant clinical activity in both BRCA-mutated and sporadic ovarian cancer, with a favorable toxicity profile. I think there really is scope now for taking it forward as potential maintenance therapy.?