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PARP Inhibitors Show Promise in Trials

TOP - December 2010, Vol 3, No 8 published on November 30, 2010

Deborah Armstrong, MD

SAN FRANCISCO—Poly(ADP-ribose) polymerase (PARP) inhibitors are showing impressive potency against ovarian cancer in early clinical trials, according to Deborah Armstrong, MD, an associate professor of oncology, gynecology, and obstetrics at Johns Hopkins University, Baltimore, Maryland.

At least eight companies are testing PARP inhibitors and one agent, iniparib (BSI-201, BiPar Sciences), is in phase 3 clinical trials with applications to the US Food and Drug Administration (FDA) clearly on the horizon, she said at the sixth annual Oncology Congress. “One of these drugs will see the light of day fairly soon and will be going to the FDA pretty quickly,” Armstrong predicted.

PARP inhibitors appear especially effective when combined with platinum drugs, but even on their own they can improve ovarian cancers in some patients, she said. And the drugs have shown some promise against breast cancer as well.

In ovarian cancer, PARP inhibitors appear most effective in patients with mutation in the BRCA1 or BRCA2 gene.

In one recent trial in patients with a BRCA1 or BRCA2 mutation and recurrent ovarian cancer (Audeh MW, et al. Lancet. 2010;376:245-251), 11 of 33 patients responded to 400-mg twicedaily olaparib. “These re sponses were maintained for a long period of time, getting close to 1 year in the average patient,” said Armstrong.

The drug appears to work by interfering with the process by which tumor cells repair themselves.

DNA damage can happen for many reasons, including platinum therapy. Cells repair single-strand DNA damage through a process called base excision repair. They repair double-strand damage through homologous recombination (otherwise known as nonhomologous end-joining).

Base excision repair depends on PARP, which binds to single-strand breaks and recruits DNA repair enzymes. Without PARP, single-strand breaks are not repaired; instead they become doublestrand breaks.

This is germane to cells with BRCA mutations, because the BRCA1 and BRCA2 genes supply proteins critical for the repair of a double-strand break. Without these proteins, a doublestrand break results in a collapsed fork and cell death.

People with BRCA gene mutations have one normal and one mutated copy of these genes. Cancers occur when the normal gene is damaged by an event such as exposure to ionizing radiation. However, only the tumor cells have two damaged copies; the body’s other cells maintain a normal copy of the gene.

If PARP is inhibited, single-strand breaks become double-strand breaks in both the tumor cells and the healthy cells. The tumor cells cannot repair this damage so they die. But the healthy cells are able to repair their DNA using homologous recombination with proteins provided by their normal BRCA1 or BRCA2 genes.

“So the tumor cells are much more sensitive to low-level PARP inhibition,” said Armstrong. “And this gives us a very nice clinical window to use.”

Because some patients without BRCA defects also respond to PARP inhibition, researchers are wondering if there could be other types of defects related to the homologous recombination pathway that repairs double-strand breaks.

Besides BRCA mutations, a somatic deletion of both BRCA genes or promoter methylation could also interrupt the pathway. Some investigators have proposed defects in other genes in volved in homologous recombination, such as RAD51. Others have suggested somatic mutations affecting the pathway.

“High-grade serous ovarian cancers may be defined by the defects in this pathway,” said Armstrong. “There have been estimates this could be in as many as 5% to 31% of ovarian cancers.”

She cited a survey reported by Doug Levine, MD, a gynecologic oncologist at Memorial Sloan-Kettering Cancer Center, New York, which found that 49% of the ovarian cancers they studied had defects in the homologous recombination pathway.

“So I think that leads us to the concept that maybe this is a good target for at least a significant minority of hybrid ovarian cancers, and potentially even the majority of high-grade serous cancers,” Armstrong said.

The latest research also supports therapies in which a PARP inhibitor is paired with platinum therapy. In a study presented last year by O’Shaughnessy and colleagues, the PARP inhibitor BSI-201 was combined with gem citabine/carboplatin in patients with triple-negative metastatic breast cancer (J Clin Oncol. 2009;27:18[suppl]:Ab stract 3). Of the 44 patients receiving only the chemotherapy, seven (16%) achieved an objective response. Of the 42 patients receiving the BSI-201 in addition to the chemotherapy, 20 (48%) responded, a statistically significant difference (P = .002).

“This is the really astounding data,” said Armstrong. “You essentially saw a tripling of the response rate.”

She added that in the O’Shaugh nessy study there was essentially no additional toxicity when BSI-201 was added to the chemotherapy. However, she warned that there are still very little data on toxicity because PARP inhibitors have rarely been matched against placebo in clinical trials.

“We have DNA repair processes for a reason,” she said. “Will we be seeing a higher rate of secondary malignancies if we are inhibiting DNA repair processes?”

She’s looking forward to that answer from the next round of research, now under way.

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TOP - December 2010, Vol 3, No 8 published on November 30, 2010
Last modified: July 22, 2021