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The Circuitous Path of PARP Inhibitor Development in Epithelial Ovarian Cancer

The Circuitous Path of PARP Inhibitor Development in Epithelial Ovarian Cancer

Ovarian cancers account for more than 50% of gynecologic cancer deaths. This is attributable to the late stage of the disease at diagnosis. Overall, 22,280 new cases of epithelial ovarian cancer and 15,500 deaths are estimated for 2012.[1] Although ovarian cancer is highly sensitive to initial platinum-based chemotherapy, with response rates of 70% to 90% in previously untreated patients, only 30% are cured by upfront surgery and chemotherapy.[2,3] The remaining cases will relapse, and cure after relapse is unlikely. Rational therapies directed toward specific molecular targets, and a better understanding of the mechanisms of action and resistance of novel agents, are urgently needed to improve survival of patients with recurrent ovarian carcinoma. Recently, PARP inhibitors, which impair the base excision DNA repair (BER) pathway, have been emerging as promising targeted therapies.

PARP Inhibitors: Preclinical Data and Rationale

Poly(ADP-ribose) polymerase (PARP) proteins are involved in DNA replication, transcriptional regulation, and DNA damage repair.[4-6] Inhibition of PARP converts common single-strand DNA breaks (SSB) into double-strand breaks (DSB) during DNA replication. In the absence of homologous recombination mechanisms (HR), inhibition of PARP results in poor repair of these lesions and apoptosis. Therefore, PARP inhibitors currently entering clinical trials have been of interest in combination with radiation and chemotherapy, and as single agents in cases of patients with deficient HR (for example, in the presence of BRCA mutations), especially in patients with breast and ovarian cancers. The concept of “synthetic lethality,” which exploits the vulnerability of cancer cells that have lost one mechanism of DNA repair (ie, deficiency in HR) by targeting a second pathway (ie, BER repair with PARP inhibitors), may be a particularly attractive therapeutic approach.

Xenograft models of other types of solid tumors (eg, cervix, colon, lung, glioblastoma, and squamous cell carcinoma of the head and neck) have shown that PARP inhibitors administered hours prior to radiation delayed tumor growth or reduced tumor volumes.[7-12] Additive or synergistic antitumor effects have been shown with cisplatin, doxorubicin, and topotecan.[13,14]

Beyond BRCA Mutation Carriers

Approximately 10% of all ovarian cancers are associated with deleterious BRCA1 or BRCA2 mutations, and up to 35% of sporadic serous ovarian cancers exhibit BRCA1 inactivation via epigenetic silencing.[15-17] Finally, other proteins involved in the homologous recombination pathway, such as ATM, MRE-11, EMSY, and the Fanconi anemia proteins are affected in 17% to 60% of patients.[18-20] Given these other mechanisms of BRCA dysfunction that profoundly sensitize cells to PARP inhibition, it may be rational to study patients with sporadic ovarian cancer displaying BRCAness, as well those with BRCA mutations. A molecular characterization study suggested that more than 50% of patients with high-grade EOC had loss of BRCA function, either by genetic or epigenetic events.[21] In addition, 60% of endometrioid ovarian tumors exhibited loss of heterozygosity at the PTEN locus.[22] PTEN-deficient tumors also have deficiency of homologous recombination repair, and preclinical data suggest profound sensitivity of PTEN-deficient tumor cells to PARP inhibitors.[23]

PARP Inhibitors: Clinical Trials

PARP inhibitors have demonstrated activity when used as single agents for patients with BRCA-associated cancers who have a deficient homologous recombination DNA repair pathway. Olaparib (AZD 2281), a PARP-1 inhibitor, has demonstrated promising results as a single agent in phase I and expansion trials.[24,25] The agent showed a high response rate in a phase II trial of 57 BRCA-positive patients. The drug was well tolerated, and the results confirmed phase I data.[26] Another phase II study of 90 patients reported a RR of 24% in high-grade serous (HGS) ovarian cancers, and a RR of 41% in BRCA-mutation carriers.[27] Lederman et al presented a randomized placebo-controlled trial of olaparib in 265 patients with platinum-sensitive relapsed ovarian cancer, and noted a statistically significant improvement in progression-free survival (PFS) in the maintenance setting.[28] Given that clinical trials of olaparib have shown no improvement in overall survival, however, the manufacturer, AstraZeneca, recently announced that there would be no further investigation of the agent in the maintenance setting for ovarian cancer. As Zorn discusses in her article, in another randomized phase II study of pegylated liposomal doxorubicin (PLD) vs olaparib there was no difference in PFS, but this may have been due to the improved sensitivity of BRCA-mutation carriers to PLD.[29]

Veliparib, a PARP 1 and 2 inhibitor, in a phase I study confirmed potentiation of topotecan's effects on DNA, with increased levels of γH2AX; however, it was noted to be too toxic and required dose de-escalation.[30] A phase I study of irinotecan and veliparib in solid tumors, including seven patients with ovarian cancer, demonstrated that the combination of irinotecan at 100 mg/m2 on days 1 and 8 with veliparib was associated with a clinical benefit.[31] Although olaparib and veliparib are the most widely studied in ovarian cancer, additional PARP inhibitors, including BSI-201, AG014699, CEP9722, MK4827, E7016, LT673, and others, are in development as noted in Zorn's review.

Difficulties in Development

Despite promising data on olaparib, it has been 3 years since the publication of the initial phase I data, and there has yet to be a large randomized phase III trial in ovarian cancer. A trial of this nature is required to obtain registration and FDA approval. As a research community, however, we have been sidetracked by the complexities of targeted therapy with PARP inhibitors. First, the notion that PARP inhibitors may potentiate chemotherapy and radiation therapy has led to combination studies, instead of a focus on single-agent trials. Second, trials have expanded patient cohorts to include HGS tumors without an approved, confirmed biomaker test to predict response to PARP inhibition. Both of these are important areas of study, but it is essential to conduct a large phase III trial in ovarian cancer patients with BRCA mutations, to definitively establish initial efficacy in the recurrent setting. This would enable many patients seeking PARP inhibitors for treatment of their ovarian cancer to gain improved access to this highly coveted class of drugs.

Further delays in drug development include the reformulation of olaparib, the most widely studied PARP inhibitor to date. Additionally, recent negative phase III data on iniparib (BSI-201) in breast cancer have decreased the enthusiasm for PARP inhibitors as a class of agents. However, it must be noted that iniparib may not be a true PARP inhibitor and does not inhibit PARP 1 and 2 like olaparib and veliparib.[32] It is hoped that, as a scientific community, we will overcome these roadblocks, learn from the complex issues encountered in their development, and regain focus to properly investigate this class of drugs to definitively establish their role in the treatment of ovarian cancer. It is a responsibility that we must take seriously, for the lives of our patients suffering from ovarian cancer are at stake. These issues are most pressing for ovarian cancer patients with BRCA mutations, a clinical setting in which the rationale for use of PARP inhibitors, and their single-agent activity, are compelling.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References

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