Drug Combo Gets Second Wind in Treating BRCA-Deficient Tumors

In a phase I study of 38 patients, a one-two punch of sapacitabine, a novel nucleoside analogue, and seliciclib, a cyclin-dependent kinase (CDK) inhibitor, has shown unexpected efficacy against BRCA-deficient solid tumors. The patients with BRCA mutations who responded to the drug combination had been diagnosed with incurable pancreatic, breast, and ovarian cancers.

“We definitely have a group of BRCA patients who appear to be benefiting from this treatment,” says Geoffrey Shapiro, MD, PhD, an associate professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA. “This needs to go into a new, much larger trial.”

Shapiro presented the study's findings at the American Association of Cancer Research Annual Meeting 2013, held in Washington, DC, April 6–10.

Sapacitabine and seliciclib were developed by Cyclacel, headquartered in Berkeley Heights, NJ. Sapacitabine causes single-strand DNA breaks that are converted to double-strand breaks during replication. The thinking going into the trial was that seliciclib, by interfering with the repair of damaged DNA, would make sapacitabine that much more cytotoxic, explains Shapiro.

Sequential administration of the drugs produced stable disease in patients without BRCA mutations during the dose-escalation phase of the study, but 2 things happened at about the same time that turned the focus to patients with BRCA mutations, Shapiro says. First, William Plunkett, PhD, a professor at The University of Texas MD Anderson Cancer Center, reported that the repair of DNA breaks caused by sapacitabine is almost completely dependent on the homologous recombination repair pathway, which includes BRCA proteins and is down-regulated when they are absent. Second, a pancreatic cancer patient in the trial had a partial response, and DNA testing showed she was a BRCA mutation carrier.

Thereafter, enrollment in the trial was limited to patients with BRCA-deficient cancers. Three more people (2 with breast cancer and 1 with ovarian cancer) had partial responses. The pancreatic cancer patient's partial response ended after 5 months, but the partial responses in the other 3 patients have lasted between 9 and 21 months, and the 3 are continuing on study treatment.

Still, only 6 out of 16 BRCA mutation carriers (the 4 partial responders and 2 with stable disease) benefited from the drug combination. Shapiro says some of the patients who didn't benefit were too ill to finish a cycle of the drugs, so they couldn't be evaluated. Others had previously developed resistance to either cisplatin or a PARP inhibitor. (The PARP pathway is involved in repair of single-strand DNA breaks.) The homologous recombination pathway may be reactivated when resistance occurs, he says, which could thwart the effectiveness of the sapacitabine-seliciclib combination.

Shapiro's prediction: “I think the drug combination is going to work best in patients who have tumors that are defective in homologous recombination, and BRCA-deficient patients are going to be the largest subset of those.”

In the study, sapacitabine and seliciclib were given sequentially; concomitant administration is now being evaluated. Shapiro says that preclinical studies are being conducted to establish the individual contributions of the 2 drugs to the activity of the combination, as well as the most effective dosing schedule.