Expert Says Olaparib Label Needs Expansion

Maurie Markman, MD

Maurie Markman, MD

The FDA’s recent approval of olaparib (Lynparza) for women withBRCA-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 aBRCAmutation 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 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 inBRCA1/2, 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 germlineBRCA(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 measurablegBRCA-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 deleteriousgBRCA-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 al⁴had reported that the median progression-free survival (PFS) was significantly longer among patients with aBRCAmutation 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 aBRCAmutation 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 aBRCAmutation, 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-typeBRCA(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 acquiredBRCA1orBRCA2mutations, epigenetic inactivation ofBRCA1, orBRCA-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 aBRCAmutation, 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.”

Moreover, Markman said, the research also demonstrates that patients with high-grade serous cancers may also respond to treatment “presumably because of a molecular signature and similar type of molecular defect” as in individuals withBRCA-mutated malignancies.

“They may not respond as well, but from an individual patient’s perspective, if they want to try this drug, I think absolutely it should be done—if they want it and they understand the data, the risk, and the benefits,” said Markman.

Markman said now that the drug is approved, oncologists would be able to assess how patients respond outside of the confines of a clinical trial. “There’s every reason to believe based upon the data that’s available that there’s a fairly large population of patients who may benefit, going all the way from the maintenance therapy setting, as described in many of the trial patients, who have potentially platinum-sensitive ovarian cancer and who have BRCA mutations or, again, maybe have high-grade serous cancer,” he said.

“If this drug is a single agent, that might be something to try even before platinum in the recurrent setting in selected patients,” added Markman. “That will have to be learned.”

Long Regulatory Road

Although the label indication is narrow, the FDA’s approval of olaparib marked the high point thus far of what has been a tortuous regulatory path for the drug.

The initial results from Study 19, which evaluated olaparib as maintenance therapy in platinum-sensitive, relapsed, high-grade serous ovarian cancer, demonstrated a PFS benefit for the drug but no significant difference in overall survival.⁵

The findings from that 2012 interim analysis had not yet been correlated with mutation status and, even before the peer-reviewed publication of the data, AstraZeneca already had announced that it was ending its development program for olaparib as a maintenance therapy in ovarian cancer.⁶Two years later, the company revived the program, based on the findings from the subgroup analysis ofBRCAmutation–positive tumors.

Olaparib’s future, however, appeared insecure again in June 2014 when the FDA’s ODAC panel recommended against approving the drug. In briefing documents, FDA staffers had expressed concern that the application relied upon a sample size from a retrospective analysis that could not reliably predict that the benefits of the therapy in a maintenance setting would outweight the risks of toxicities, such as myelosuppression, fatigue, and gastrointestinal disturbances.⁷

The briefing document noted that, instead of granting an accelerated approval for the drug, the FDA could wait for the results of the SOLO2 trial, which is evaluating olaparib maintenance monotherapy versus placebo in relapsedBRCA-mutated ovarian cancer.⁷Although the trial design is similar to that of Study 19, a key difference is in the dosing of olaparib. The drug, initially given as a 400-mg capsule twice daily, has been reformulated into a 300-mg tablet twice-daily dose that is expected to offer increased bioavailability with a lower incidence of anemia.⁷

After a negative 11-2 ODAC vote, AstraZeneca said it submitted “a major amendment” to its New Drug Application, offering additional data that the FDA had requested and ultimately gaining the approval.

Ongoing Clinical Trials

In order for olaparib to make the transition to full regulatory approval, the FDA will conduct a review of data from either of two ongoing phase III trials, AstraZeneca said.²

Along with SOLO2, the company has launched the SOLO3 trial in which olaparib is being compared with non-platinum chemotherapy as a third-line or later treatment for patients with relapsed ovarian cancer and agBRCAmutation. SOLO2 data are expected this year, while SOLO3 findings are anticipated in 2019.

For his part, Markman believes olaparib should have been approved 3 years ago when the PFS data from the phase II trial were reported. PFS is the primary outcome measure in both the SOLO2 and SOLO3 trials.

Olaparib, Markman said, is “an extremely important advance and it’s extremely important that it's available to patients.”

“It is patients who should decide whether this is a reasonable drug for them in this setting, and they need to be absolutely, without any question, the final arbitrators on this particular issue, not the regulators and not the oncologists,” said Markman. “Their oncologists need to explain the risk and the benefits very clearly, and the patients should have the opportunity to make that decision along with their advisers, including their family and their doctors.

“The management should not be determined by the FDA or any other regulatory agency,” he added. “It should be done by clinicians working with patients.”

References

1. Lynparza [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2014.
2. LYNPARZAâ„¢ approved by the US food and drug administration for the treatment of advanced ovarian cancer in patients with germlineBRCA-mutations [press release]. London, England: AstraZeneca; December 19, 2014.
3. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germlineBRCA1/2mutation [published online November 3, 2014].J Clin Oncol. 2015;33(3):244-250.
4. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial [published online May 31, 2014].Lancet Oncol.2014;15(8):852-861.
5. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.N Engl J Med. 2012;366(15):1382-1392.
6. AstraZeneca updates on olaparib and TC-5214 development programmes [press release]. London, England: AstraZeneca; December 20, 2011.
7. US Food and Drug Administration. FDA briefing document Oncologic Drugs Advisory Committee meeting on June 25, 2014. http://goo.gl/TrntXX. Published June 2014. Accessed April 13, 2015.