Is There a Future for PARP Inhibitors in Ovarian Cancer?

Poly(ADP-Ribose) polymerase (PARP) inhibitors are very promising agents, particularly when it comes to the potential treatment of cancers associated with the inherited BRCA gene mutations. Interest in these drugs peaked particularly with the New England Journal of Medicine publication of a phase I trial of one of these agents, AZD2281, also known as Olaparib (1). In that trial, 12 of 19 BRCA mutation carriers (63%) had a clinical benefit, including durable responses in nine of these patients.

Since then, we have been actively investigating this agent in BRCA associated breast and ovarian cancers. One seminal trial in ovarian cancer was just presented by Dr. Stanley Kaye at this year's meeting of the European Society of Medical Oncology (ESMO) (2).

In this study, 97 patients with BRCA mutation associated ovarian cancer, who had progressed or recurred within 12 months of platinum-based treatment, were randomized to Olaparib versus a commonly used agent, pegylated liposomal doxorubicin (PLD). These patients had received a median of 3 prior treatments, but there was no cap on prior regimens and in this study, a maximum of 11 prior treatments was recorded. Patients randomized to Olaparib were treated with one of two planned doses of the drug and the primary end point of the study was to determine how long patients went before the disease progressed, or the progression- free survival (PFS).

Professor Stanley Kaye presented the results at ESMO. The main outcome was that Olaparib failed to show a benefit in PFS at the low dose (200 mg) or high dose (400 mg) versus PLD with median PFS reported of 6.5 vs 8.8 vs 7.1 months, respectively. There were no complete responses recorded, but 25% (8/32 women) in the low dose group, 32% (10/31) in the high dose group, and 18% (6/33) treated with PLD reported a partial response. When clinical benefit is considered (response and those who had no disease progression reported for at least four months) the results were 66%, 68%, and 58%, respectively. There was no difference seen in overall survival among the treatment arms nor were differences in quality of life seen.

These results are sobering in so far as Olaparib did no better than chemotherapy in an enriched population of BRCA mutation carriers with ovarian cancer. What is unclear, even still, is whether the results are due to treatment heterogeneity, given that prior therapies varied substantially. Still, this study demonstrates how much more we need to learn about utilizing PARP inhibitors in ovarian cancer, and this study specifically raises more questions than answers.

I do believe the PARP inhibitors will be important agents in the treatment of BRCA associated malignancies, and potentially, of other cancer types as well (see article 3 by my colleague Dr. PA Konstantinopoulos on BRCAness). Further research (already ongoing) will help to clarify the role and best approach to the use of these agents in future therapy of human malignancy.

References:

1. PC Fong, et al. Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA mutation carriers. NEJM 2009;361:123-34.

2. S Kaye, et al. Phase II study of the oral PARP inhibitor Olaparib (AZD2281) versus liposomal doxorubicin in ovarian cancer patients with BRCA1 and/or BRCA2 mutations. ESMO 2010; Late Breaking Abstract. Milan, Italy.

3. PA Konstantinopoulos, et al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncology 2010;28:3555-61.