At last year's ASCO Annual Meeting, the class of agents capable of inhibiting poly (adenosine diphosphate-ribose) polymerase-ie, PARP inhibitors-was moved to the forefront in the minds of many oncologists. This occurred when investigators announced preliminary findings for two investigational compounds in triple-negative tumors and those deficient in the BRCA gene.

The data prompted Eric Winer, MD, of Dana-Farber Cancer Institute, who served as a discussant on the topic at ASCO, to comment, "PARP inhibitors will likely be a major advance. When you go home [from ASCO], you can be really excited about this."

This month, as the ASCO 2010 Annual Meeting takes place, these drugs are on every clinician's radar, the hope being that they will offer patients with triple-negative and BRCA-deficient breast cancer a real chance at prolonged survival. The ASCO Post followed up on the pivotal findings from 2009 to see how far this field has come in a year.

BSI-201 Findings 'Spectacular'

PARP is important for DNA base-excision repair. High expression of PARP has been found in DNA-unstable breast cancers, including BRCA1-mutated and triple-negative tumors.

BSI-201 (BiPar Sciences) is the first of the new class of PARP inhibitors. At the 2009 San Antonio Breast Cancer Symposium, Joyce O'Shaughnessy, MD, of US Oncology, Texas Oncology, and Baylor Sammons Cancer Center, Dallas, reported that triple-negative breast cancer patients receiving intravenous BSI-201 in addition to gemcitabine (Gemzar)/carboplatin had a median survival of 12.2 months compared with 7.7 months for chemotherapy alone, without additional toxicity. The findings came from further follow-up of a study of 120 patients with metastatic disease that she first reported at ASCO.

"The results are spectacular," commented Peter Ravdin, MD, of The University of Texas Health Science Center at San Antonio and a member of the symposium program. He pointed out that while response rates to chemotherapy were a predictable 16%, they jumped "strikingly" to 48% with the addition of the PARP inhibitor, and response duration doubled.

Lee Schwartzberg, MD, of the West Clinic, Memphis, Tennessee, noted that the 50% reduction in mortality was especially striking since many patients crossed over to receive the investigational agent upon progression. "A significant number of patients are still alive 18 months after starting therapy," he noted. "And surprisingly, the addition of BSI-201 had a negligible effect on toxicity. Obviously, it is of great interest to see substantial benefit with minimal incremental toxicity."

In an interview with The ASCO Post, Dr. O'Shaughnessy said a database lock on the phase II trial is in place for May/June, with a final analysis planned for soon thereafter. Data will not be presented at the ASCO Annual Meeting this year.

A similarly designed phase III FDA registration trial of 420 patients was launched in July 2009 and has completed accrual, its primary endpoints being progression-free and overall survival.

Dr. O'Shaughnessy commented that the study had an extremely fast enrollment, with 110 sites participating. "There was huge demand to be part of this trial," she said.

Oral PARP Inhibitor: Olaparib

Also hailed at ASCO 2009 was the oral PARP inhibitor olaparib (AstraZeneca). In an open-label dose-finding phase II trial of 60 advanced breast cancer patients with BRCA1 or BRCA2 mutations, all heavily pretreated, one-third of the women demonstrated tumor shrinkage, reported Andrew Tutt, MD, PhD, Director of the Breakthrough Breast Research Unit of Kings College in London. Median time to disease progression was 5.7 months in patients receiving 400 mg and 3.8 months in the 100-mg cohort.

The estimated filing date for FDA approval is 2012, according to the company website.
James Carmichael, BSc, MBChB, MD, Medical Science Director at AstraZeneca, said the company intends to start a phase III study in BRCA-mutated breast cancer. In addition, he said that numerous randomized phase II studies are ongoing.

"And at this year's ASCO there will be a number of abstracts," he said. These include an oral presentation based on translational research to assess the efficacy of single-agent olaparib in serous ovarian cancer [abstract 3002] and other reports from studies to define the optimal dose and schedule for olaparib in combination with chemotherapy [abstracts 1018, 3027, and 5041].

PARP Activity Not Limited to Uncommon Phenotypes

Equally intriguing this year was news that broke during the European Breast Cancer Conference: PARP is not limited to patients with triple-negative or BRCA-deficient tumors.

"PARP is present in all hormone-receptor and HER2 phenotypes," according to Gunter von Minckwitz, MD, of the German Breast Group in Neu-Isenburg.

In a retrospective analysis of tissue specimens obtained during a clinical trial of neoadjuvant chemotherapy, PARP levels predicted response to chemotherapy, with pathologic complete response rates increasing as PARP expression increased.

Dr. von Minckwitz and colleagues rated 638 specimens as having low, medium, or high PARP expression. PARP expression was present regardless of hormone receptor or HER2 status. High cytoplasmic PARP expression correlated with aggressive tumor patterns like nonlobular histology, higher grade, and nodal involvement, whereas nuclear expression did not. Tumors with high cytoplasmic PARP expression had a much higher chance for a pathologic complete response than tumors with a low expression. Tumor grade virtually lost its significance in favor of PARP expression as an independent predictor of pathologic complete response, Dr. von Minckwitz noted.

"We will present data on the prognostic value of PARP expression in terms of long-term outcome at this year's ASCO Annual Meeting," Dr. von Minckwitz offered. "It would be fair to say that PARP-positive breast cancer might become a new, clinically relevant entity, and we believe we may be on the verge of a major change in the way breast cancer is treated."

Dr. O'Shaughnessy commented on these findings. "This bolsters the idea that elevation of PARP expression is probably a marker for genomic instability in general, and PARP inhibitors need to be evaluated in other genomically unstable breast cancers. This is a big need, and multiple trials are planned."

Looking Ahead

The findings of the past year have led to robust clinical development, with at least seven PARP inhibitors now in development, according to Dr. Schwartzberg (Table 1).

"But there is no free lunch," he acknowledged. It appears there may be secondary BRCA2 mutations that can restore BRCA expression and function, thus causing resistance to PARP inhibitors. While this is a question to be explored down the road, he added, "the fact that we already know about this is favorable because we can start to design studies that exploit the mutation status."

Dr. Schwartzberg predicts that PARP inhibitors may have roles in additional settings and subsets of patients since they enhance the activity of other DNA-damaging agents, ie, platinums, alkylators, and topoisomerase inhibitors. "There is reason to believe that PARP inhibition may be a broad, generalizable phenomenon that could add benefit to other drugs," he said.

Other questions to answer involve the optimal timing of PARP inhibition relative to the cytotoxic agent, the optimal dose and schedule, and optimal duration of treatment.

"Obviously, these are questions that will be answered once clinical utility is established," Dr. Schwartzberg said. "Meanwhile, I am very excited. I believe PARP inhibition fulfills the paradigm of personalized medicine."