The genomic instability inherent in serous ovarian cancer poses treatment challenges, but it also represents a target which can be exploited through the use of PARP inhibitors
Michael J. Birrer, MD, PhD
The genomic instability inherent in serous ovarian cancer poses treatment challenges, but it also represents a target which can be exploited through the use of PARP inhibitors, according to Michael Birrer, MD, PhD, professor of Medicine, Harvard Medical School, and director of Gynecologic Medical Oncology at Massachusetts General Hospital in Boston.
“There is a plethora of data suggesting that serous ovarian cancers represent tumors of genetic chaos,” Birrer noted in his presentation at the 9th Annual International Symposium on Ovarian Cancer and Gynecologic Malignancies. “The question is: what do we do about it?”
Inhibiting PARP makes sense in ovarian tumors which arise from DNA repair abnormalities, Birrer explained, because PARP detects and works to repair these single-strand breaks in DNA. Thus, for example, in a woman who has inherited a germ line BRCA mutation and develops ovarian cancer, inhibiting PARP in those cells should result in doublestranded breaks, and the cells will die through a process which has been described as “synthetic lethality.”
Birrer pointed to phase I and II studies of the PARP inhibitor olaparib demonstrating antitumor activity in cancers associated with a BRCA1 or BRCA2 mutation that generated a lot of excitement about the oral agent, which also proved to be generally well tolerated by patients (N Engl J Med. 2009;361:123-134; Lancet. 2010;376:245-251). Some subsequent studies of the agent, however, had mixed results, and study design was a factor, Birrer noted (J Clin Oncol. 2012;30:372-379; N Engl J Med. 2012;366:1382-1392).
One outcome of the research was the finding that olaparib can be combined with chemotherapy, although Birrer is not sure that such a dose-intense approach makes sense. “What you’re doing is beating a cell over the head with a platinum compound. You’re coming back with PARP inhibiting the repair of the DNA.”
Currently, a number of PARP inhibitors, in addition to olaparib, are in clinical development or moving out of the laboratory into the clinic, said Birrer. Of these, he said, BMN-673 has “very good data,” indicating that it is much more potent than others in development, though whether this means the agent will be more effective or more toxic is not yet determined.
Given the interesting data reported for the most studied agent, olaparib, and the many other PARP inhibitors now in development, Birrer discussed the implications for patients with serous ovarian cancers.
“We know it’s certainly going to work for the 8% to 10% of women who have a family history and BRCA 1/2 mutations. It will probably work for the additional 8% who walk in the clinic with a sporadic cancer but also have a germline mutation. It’s probably going to work for the additional 5% or 6% of women with ovarian cancer that has some other mutation germline in the Fanconi pathway. And, it will probably work for an additional 5% to 10% of patients who have no germline mutation but the tumor itself has a somatic abnormality in BRCA 1.
“You add those numbers up, it gets reasonably exciting,” said Birrer. He pointed to a 2011 Canadian study by Gelmon and colleagues, which found olaparib resulted in a 24% response rate in patients with ovarian cancer but who had non-BRCA mutation status, as well as a 41% response rate in participants with the germline mutation (Lancet Oncol. 2011;12:852-861). He also cited research indicating a possible role for PARP inhibitors in PTEN-deficient endometrial cancer, as well as data supporting the use of PARP inhibitors as radiation sensitizers (Nat Rev Clin Oncol.2011;8:302-306). “As you can imagine, radiation damages DNA and inhibiting PARP would make a lot of sense.”
“PARPs are important, PARPs are here, and there are a lot of trials coming down the pike,” Birrer concluded. Two phase III olaparib trials should be open soon under the auspices of the Gynecologic Oncology Group, he said, as well as a randomized phase III trial of niraparib as maintenance in platinum-sensitive ovarian cancer patients. Other trials for rucaparib are also gearing up.
Even if patients are not mutation carriers, he advised, “and you think they might benefit from a PARP inhibitor, there should be no shortage of trials, and you should avail yourself of those.”