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Ovarian Cancer Expert Says Olaparib Label Is Too Restrictive

Anita T. Shaffer @Shaffer1
Published: Wednesday, Apr 15, 2015

Dr. Maurie Markman

Maurie Markman, MD

The FDA’s recent approval of olaparib (Lynparza) for women with BRCA-mutated advanced ovarian cancer marks a significant therapeutic advance for women with the malignancy, but the specific indication is far too restrictive and the drug should be offered to many more patients, according to Maurie Markman, MD.

In fact, Markman said, clinical trial evidence indicates that some women with high-grade serous ovarian cancer who do not test positive for a BRCA mutation also may respond to olaparib, and they should have an opportunity to decide in consultation with their physicians whether the drug is appropriate for them.

“I applaud the FDA for approving the drug, but the language in the approval is far too restricted based on the data,” said Markman, a specialist in gynecologic malignancies who is president of Medicine & Science at Cancer Treatment Centers of America. “There are a variety of clinical indications one could consider that are extremely rational and that should be discussed with patients.“

The complexities that Markman, who also is editor-in-chief of OncologyLive magazine, raised in an interview reflect some of the hurdles that olaparib has had to surmount on its path to regulatory approval in December 2014.

Olaparib is a first-in-class inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, which are active in DNA transcription and repair. The oral agent has proved most effective against tumors with mutations in BRCA1/2, tumor suppressor genes whose best-understood role is the repair of double-strand breaks in DNA.

The FDA granted an accelerated approval to olaparib as monotherapy in patients with advanced ovarian cancer whose tumors test positive for deleterious or suspected deleterious germline BRCA (gBRCA) mutations and who already have been treated with three or more prior lines of chemotherapy. The BRACAnalysis CDx test was approved as a companion diagnostic.

The olaparib approval was based on a 34% objective response rate and a 7.9-month median duration of response among 137 patients with measurable gBRCA-mutated ovarian cancer who received olaparib monotherapy after ≥3 lines of chemotherapy.1

Broader Implications in Study

The pivotal findings stemmed from a single-arm phase II study of olaparib in patients with deleterious or suspected deleterious gBRCA-mutated advanced cancers, and on safety data from several other olaparib studies, according to AstraZeneca, the company developing the drug.2,3

Previously, Ledermann et al4 had reported that the median progression-free survival (PFS) was significantly longer among patients with a BRCA mutation who had received olaparib compared with placebo (11.2 vs 4.3 months, respectively; P <.0001). Study 19, as the trial has been called, randomized 265 participants to olaparib or placebo from August 2008 to February 2010.4

Notably, 14% of the patients with a BRCA mutation had aberrations of somatic (acquired) origin, as opposed to germline mutation. Investigators said this patient group was too small to analyze formally, but that the outcomes suggest that olaparib is “most effective in tumours with a BRCA mutation, irrespective of whether the mutation originates in the germline or tumor DNA.”3

Additionally, the researchers found that PFS was longer with olaparib versus placebo among patients with wild-type BRCA (7.4 vs 5.5 months, respectively; P = .0075), although not as pronounced as among those with the aberration.

The responses illustrate the complexity of the signaling pathways at work in ovarian cancer. “Up to 50% of patients with high-grade serous ovarian cancer are deficient in homologous recombination—a key pathway for repair of DNA damage—due to germline or somatically acquired BRCA1 or BRCA2 mutations, epigenetic inactivation of BRCA1, or BRCA-independent defects in the homologous recombination pathway,” according to Ledermann and colleagues.4

That pool of patients is much deeper than the number of women with ovarian cancer whose tumors harbor a BRCA mutation, which is estimated at up to 15% of all cases.2

Rationale for Expanded Usage

Markman said olaparib should be used more widely than the label indication for two reasons: (1) if a patient has a BRCA mutation, it is not relevant whether that mutation is germline or somatic; and (2) Ledermann et al’s findings show that patients without specific BRCA mutations also can benefit from the drug.

On the mutation point, Markman noted that a number of companies developing BRCA tests today are doing so based on tumor DNA. “They cannot tell you whether it’s in the germline—and that is completely biologically irrelevant anyway,” said Markman. “It’s the presence of the mutation that is important, not whether it’s germline.”


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