A New Hope

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CURE, Fall 2010, Volume 9, Issue 3

PARP inhibitors continue to look “promising.”

The new year could bring good news to some patients with triple negative breast cancer, ovarian, prostate and maybe other malignancies.

That’s when researchers hope to see the results of a phase 3 clinical trial in one of the most promising new classes of drugs to come along in cancer treatment in a while. The drugs—PARP inhibitors—dominated the 2009 American Society of Clinical Oncology (ASCO) meeting, with study results showing the drugs are effective in certain types of breast cancers that are hard to treat. Interest intensified over the past year. The federal clinical trials database now lists at least two dozen studies involving PARP inhibitors, primarily targeted at breast, ovarian, and prostate cancers. “Everybody is very intrigued by this approach, absolutely—this is a very hot topic,” says Miguel Villalona-Calero, MD, director of solid tumor experimental therapeutics at The Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

Research is moving quickly to better understand the drugs, which are designed to block a key enzyme, poly (ADP—ribose) polymerase. PARP, as the enzyme is better known, is influential in DNA repair.

Some of the most widely discussed data involve the drugs BSI-201 (iniparib) and olaparib, but other names are being added to the developmental pipeline, including ABT-888 (veliparib) and MK4827.

PARP inhibitors are believed to work by blocking one of several critical enzymes in the body’s DNA repair mechanisms. Cells damaged by chemotherapy naturally try to repair themselves. Research suggests that some of those cells can be prevented from repairing themselves if the PARP enzyme is blocked. People with a BRCA mutation may particularly benefit from the new class of drugs because one of their other repair mechanisms has already been disabled.

“Everything is trending in a very promising direction,” says Joyce O’Shaughnessy, MD, regarding her preliminary findings regarding BSI-201 in triple-negative breast cancer patients. O’Shaughnessy, who is the co-chair of breast cancer research at Baylor Charles A. Sammons Cancer Center in Dallas, gave last year’s presentation at ASCO. She provided results of an interim analysis of a randomized phase 2 trial testing the addition of BSI-201 to chemotherapy at the December 2009 San Antonio Breast Cancer Symposium (SABCS). Those findings showed a big effect on delaying recurrence and improving survival at a level not previously seen with other drugs. But, she adds: “Until you see the results of that phase 3 trial, you just don’t know.”

Everything is trending in a very promising direction.

Some women with triple-negative breast cancer aren’t waiting. Interest was “off the charts” for the multi-center phase 3 study for BSI-201, which has already completed its enrollment of more than 420 people, O’Shaughnessy says. Also this year, Food and Drug Administration officials announced an expanded access protocol for BSI-201, specifically for women with triple-negative breast cancer who have exhausted other treatment options.

One of the women who enrolled is Sue Ross, whose doctor added BSI-201 to her Gemzar (gemcitabine) and carboplatin regimen. The 62-year-old from Dallas was diagnosed with stage 1 breast cancer in August of 2006 and underwent a lumpectomy. Additional testing showed no further signs of cancer.

But the malignancy roared back nearly three years later, when Ross developed swelling under her right arm and a nagging cough. In the spring of 2009, she was diagnosed with stage 4 triple-negative breast cancer. Tests found 43 lesions on her liver and roughly a dozen in her lungs. When a cancerous rash appeared on her right arm, her oncologist had a suggestion.

“I know of a clinical trial that I think you are a prime candidate for,” Ross recalls her doctor saying.

After several months in the trial, Ross doesn’t know if BSI-201 has made any difference, although she describes the results from imaging scans this spring as encouraging. The liver and the lung lesions had shrunk to the point where they looked more like scars, she says.

Researchers studying PARP inhibitors have primarily focused on two patient categories. One includes individuals such as Ross, who have been diagnosed with triple-negative breast cancer (meaning the tumor didn’t test positive for estrogen, progesterone, or HER2). The second group involves individuals who carry a BRCA1 or BRCA2 mutation, although a broader category is beginning to be studied: those whose tumors have a dysfunction in the BRCA pathway even though there is no BRCA mutation.

The studies use a variety of designs, and they target different groups of patients in terms of malignancy and BRCA mutation status. Some studies, such as the one that involves Ross, combine a PARP inhibitor with a chemotherapy regimen. At the SABCS meeting, O’Shaughnessy reported updated phase 2 findings showing a median overall survival of 12.2 months when the BSI-201 was combined with Gemzar and carboplatin versus 7.7 months with chemotherapy alone.

Other research assesses the new class of drugs when used alone. In one phase 2 study presented at this year’s ASCO meeting, Karen Gelmon, MD, of the British Columbia Cancer Agency described how some of the 64 women with advanced ovarian cancer responded to the oral PARP inhibitor olaparib regardless of whether they tested positive for the BRCA mutation. (The response rate was 41.2 percent for those with BRCA mutations and 23.9 percent in patients without.) An additional group of 24 women with triple-negative breast cancer didn’t respond regardless of mutation status.

Researchers are still in the learning stages of understanding how PARP inhibitors work and which BRCA pathways they target, says Kristin Zorn, MD, a gynecologic oncologist with the Magee-Womens Hospital of the University of Pittsburgh Medical Center, which is involved in a multi-center study looking at PARP inhibitor ABT-888. “Are they powerful enough to work on their own, or do they have to be combined with traditional chemotherapy or with other targeted agents?” Zorn says.

Another possibility is whether the drugs might prove beneficial in tumors that have developed a mutation in their BRCA pathway, even if the individual doesn’t test positive for an inherited mutation, Zorn says. That potential vulnerability, dubbed “BRCAness,” could open the door to a larger group of patients who might respond to PARP inhibitors, she says.

Zorn points to research presented at this year’s ASCO meeting, in which researchers described their progress in identifying a gene expression profile for BRCAness in ovarian cancer. Their research, published later that month in the Journal of Clinical Oncology, also found indications that patients with the BRCA-like profile responded better to chemotherapy.

At least 20 PARP inhibitors are in development, from early research through clinical trials, according to a mid-2010 search by the trade group PhRMA through the Adis R&D Insight database. The drugs come in various forms, including intravenous and pills. Currently, all access is limited to research trials.

While breast and ovarian cancer have garnered most of the scientific scrutiny to date, some researchers have begun to look at the influence of PARP inhibitors on other BRCA-deficient tumors or if testing of other genetic pathways could identify additional patients who might benefit.

One multi-center phase 1 study, for example, is assessing the safety of BSI-201 in solid tumors, including sarcoma, non-small cell lung cancer, and pancreatic cancer.

Another very early-stage research trial, led by The Ohio State University Comprehensive Cancer Center, is looking beyond BRCA to whether a broader category of patients could be targeted.

Besides determining which drugs work the best, with the least toxic effects, researchers also need to better isolate which patients are the best candidates.

It’s a lot of excitement and scrutiny involving a class of drugs that has no published phase 3 data. Zorn, echoing other researchers interviewed, cautions that no evidence points to a PARP inhibition—related cure. “But we may have a significant advance in treatment that will slow the progression of the disease and help patients live longer and feel better while they are living longer,” she says.

Ross is one of those patients who is living longer and better. She’s regained sufficient energy to enjoy some of life’s small pleasures, including “retail therapy,” as she jokingly calls shopping. More importantly, she’s been strong enough to make the five-hour trip to Lubbock, Texas, so she can visit with her daughter and cuddle her two young grandchildren.

Enthusiasm aside, many questions remain, rsearchers say. Besides determining which drugs work the best, with the least toxic effects, researchers also need to better isolate which patients are the best candidates.

And, there’s some concern that the drugs might lead to later cancers, given that they interfere with the body’s DNA repair mechanism, says Eric Winer, MD, chief of the division of women’s cancers at Dana-Farber Cancer Institute.