PARP INHIBITORS FROM BENCH TO CLINIC

June 25, 2009 — Early results in breast cancer with a new class of drug, which inhibits PARP, or poly(adenosine-disposphate-ribose) polymerase, have created an astonishing amount of excitement, considering that the investigational drugs will not reach the market for some time yet.

The latest enthusiasm comes from the findings of phase 1 trial with the PARP-1 inhibitor olaparib (AstraZeneca), published online June 24 in the New England Journal of Medicine, which indicate that the agent has antitumor activity in breast, ovarian, and prostate cancers associated with BRCA1 and BRCA2 mutations.

However, there was also considerable enthusiasm for these new agents at the recent American Society of Clinical Oncology (ASCO) meeting, where phase 2 results with olaparib were presented, and where phase 2 results with another PARP-1 inhibitor, BSI-201 (BiPar Sciences), were chosen for a plenary session. One expert at the meeting described the PARP inhibitors as "very promising" and singled out the BSI-201 trial as "one of the most exciting findings in breast cancer in a long time," as previously reported by Medscape Oncology.

Now an editorial in the New England Journal of Medicine notes that phase 1 trial results, such as those with olaparib, usually don't merit space in prestigious journals, but these are unusual circumstances.

Editorialists J. Dirk Iglehart, MD, and Daniel P Silver, MD, PhD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, say that "readers may be surprised by the editors' decision to publish a small early-stage trial, but this trial not only reports important results — it also points to a new direction in the development of anticancer drugs."

The thrust of modern anticancer drug development is in finding agents with few adverse effects "by leveraging advances in the understanding of cancer biology," write the editorialists. To date, it appears that PARP-1 inhibitors are case studies in doing just that.

In short, the inhibitors, which reflect a strategy of drug development known as "synthetic lethality," show antitumor activity without the toxicity associated with conventional chemotherapy.

Clinical Benefit With Minimal Adverse Effects

In the just-published phase 1 study of olaparib,12 of 19 patients who were BRCA carriers and had ovarian, breast, or prostate cancer had some measure of clinical benefit, and 9 had responses according to RECIST criteria. Furthermore, the drug had an "acceptable" adverse-effect profile, write the authors, led by author Peter C. Fong, MD, from the Royal Marsden National Health Service Foundation Trust in Sutton, England. They also write that the "adverse effects that were at least possibly related to olaparib were largely of grade 1 or 2."

In a phase 2 study of olaparib presented at ASCO, conducted in women with BRCA1 or BRCA2 mutations and advanced breast cancer that persisted despite previous treatment, more than one third of patients had tumor shrinkage. In another study of olaparib presented at the meeting, one third of 33 women with advanced chemotherapy-refractory ovarian cancer who were treated with a 400 mg daily dose of the drug had response according to RECIST.

However, at the meeting, these results with olaparib were overshadowed somewhat by the news about BSI-201, which was more prominent because the findings were presented at a plenary session, an usual forum for phase 2 results.

In combination with conventional chemotherapy, BSI-201 significantly improved overall and progression-free survival in women with metastatic triple-negative breast cancer, compared with chemotherapy alone, as reported by Medscape Oncology.

The adverse events associated with the combination of BSI-201 and chemotherapy were similar to those associated with chemotherapy alone, said investigator Joyce O'Shaughnessy, MD, from Baylor Charles A Sammons Cancer Center in Dallas, Texas, at ASCO. "BSI-201 does not add toxicity," said Dr. O'Shaughnessy.

New Direction Defined: Synthetic Lethality

PARP-1 is an enzyme involved in DNA repair, especially in the repair of tumor cells, Dr. O'Shaughnessy explained.

Agents that act as inhibitors of PARP-1 effectively disarm the ability of cancer cells to repair themselves and cause the death of those cells, write the editorialists, Drs. Iglehart and Silver.

Importantly, PARP inhibition, which kills cancer cells, spares identical normal cells that lack cancer-related alteration, such as those of mutated BRCA1 and BRCA2.

This strategy relies on synthetic lethality, observe the editorialists. "Two genes are said to be in a synthetic lethal relationship if a mutation in either gene alone is not lethal but mutations in both cause the death of a cell," they write.

Thus, a target gene needs to be discovered that, when mutated or inhibited chemically, kills cells that harbor a specific cancer-related alteration, they continue.

In cells that carry BRCA1 and BRCA2 mutations, 1 of the 2 major DNA repair methods, known as homologous recombination, is nonfunctional. However, the other major repair method, known as base-excision repair, compensates for that loss. PARP-1 inhibition disables that base-excision repair. Thus, the PARP-1 enzyme is a target that, once hit and inhibited, leads to cell death.

Cancer patients with BRCA1 and BRCA2 mutations are not the only candidates for PARP-1 inhibition, say the editorialists.

"There are almost certainly other tumors with defects in homologous recombination that should make them targets for PARP inhibition therapy," they write.

For instance, BSI-201, which has shown efficacy in triple-negative breast cancer, is also being studied in uterine and brain tumors, according to the BiPar Sciences Web site.

Olaparib and BSI-201 are but 2 of a number of PARP inhibitors being developed currently, the list of which includes AGO14699 (Pfizer), ABT-888 (Enzo), and MK4827 (Merck).

The olaparib study was supported by KuDOS Pharmaceuticals, which is owned by AstraZeneca. Some of the investigators in the study may benefit financially from patents held on PARP inhibitors. Other investigators are employees of the drug companies involved.

New Engl J Med. Published online before print June 24, 2009.