FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy

Therapy for relapsed ovarian cancer is dependent on the interval between the date of the final dose of initial therapy and date of relapse, with platinum-sensitive ovarian cancer being defined as relapse that occurs more than 6 months from the date of the last dose of platinum-based chemotherapy (1). Multiple options exist for relapsed ovarian cancer; however, data are limited on the response rates for therapy in the fourth-line setting regardless of platinum sensitivity. Several institutions have described their experience with third-line chemotherapy regimens, and the response rates ranged from 5% to 40% (2–5). There are no agents specifically approved in this disease setting.

The BRCA genes BRCA1 and BRCA2 encode proteins involved in the DNA damage repair pathway. Deleterious mutations of BRCA1 and BRCA2 are associated with an increased risk of the development of breast and ovarian cancers; however, not all mutations are considered to be deleterious (6, 7). The majority of deleterious mutations are protein-truncating mutations. Missense mutations and large rearrangements of DNA segments within the BRCA genes also result in loss of function. It is estimated that the incidence of deleterious germline BRCA mutation (gBRCAm)-associated ovarian cancer is approximately 10% to 15% of all cases of ovarian cancer, corresponding to an annual incidence of approximately 2,000 cases per year in the United States (8, 9).

Patients with gBRCAm-associated ovarian cancer are treated no differently than patients without a deleterious mutation, but the presence of a mutation appears to be positively correlated with increased survival and responsiveness to chemotherapy (10–12). Because of the increased susceptibility to chemotherapy, it is expected that the patient with gBRCAm-associated ovarian cancer will be exposed to multiple lines of chemotherapy, and cumulative toxicity is a key concern in heavily pretreated patients.

Olaparib is an inhibitor of the mammalian PARP enzyme. Its chemical name is 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]phthalazin-1(2H)-one. Olaparib is available in 50-mg capsules for oral administration.

In vitro studies have shown that olaparib inhibits various isoforms of PARP, including PARP1, PARP2, and PARP3. Olaparib inhibits growth of selected tumor cell lines in vitro and decreases tumor growth in mouse xenograft models of human cancer. Increased cytotoxicity and antitumor activity following treatment with olaparib were noted in vitro and in mouse tumor models with cell lines deficient in BRCA. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of the PARP–DNA complex, resulting in disruption of cellular homeostasis and cell death (13).

Repeat-dose toxicology studies evaluated the effects of daily doses of oral olaparib in rats and dogs for up to 26 weeks. The major target organ was the hematopoietic system, with reduced red cell mass and leukopenia reported in rats and dogs at ≥2% and 4%, respectively, of the human AUC at the recommended clinical dose. Gastrointestinal toxicities (discoloration, congestion, hemorrhage, and inflammation) were considered minimal in severity and noted in 4- and 26-week repeat-dose toxicity studies in dogs at ≥4% of the human AUC at the recommended clinical dose.

In embryo–fetal development studies, olaparib was embryotoxic and teratogenic when administered to pregnant rats during the period of organogenesis.

BRCA and PARP are key components of the DNA damage repair pathway. Specifically, both BRCA1 and BRCA2 proteins critically interact with Fanconi Anemia proteins in the homologous recombination pathway (14). Limited data exist regarding the increased risk for the development of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) in patients with germline BRCA mutations; however, because of the interactions among BRCA1, BRCA2, and Fanconi Anemia proteins, BRCA deficiency may increase the risk for the development of MDS/AML (15). The addition of further DNA damage induced by chemotherapy or other environmental factors, coupled with further impairment of a compensatory repair pathway by means of PARP inhibition, may prime patients with germline DNA repair deficiencies for the development of MDS/AML.

Following oral administration of olaparib, absorption is rapid, with peak plasma concentrations typically achieved between 1 and 3 hours after dosing. Steady-state exposures are achieved within 3 to 4 days. The mean half-life of olaparib is 12 hours at the 400-mg dose with an accumulation ratio of 1.4 with twice daily dosing. A high-fat meal did not increase the exposure of olaparib significantly; therefore, olaparib can be dosed without regard to food intake.

The results from the oral mass balance trial suggest that metabolism is an important elimination pathway for olaparib, but the contribution of the renal route cannot be ruled out. At the level of 30 mL/min or higher, creatinine clearance (CLcr) had no influence on the exposure of olaparib. Data are not available in patients with CLcr less than 30 mL/min, patients on dialysis, or patients with baseline serum bilirubin > 1.5 × ULN.

The maximum tolerated dose of olaparib was identified as 400 mg twice daily based on safety assessments in a phase 1 study. In other trials with olaparib, an exposure–response relationship was identified for anemia in the dose range of 100 to 400 mg twice daily showing an increased risk of anemia with increase in olaparib steady-state concentrations.

Olaparib is primarily metabolized by CYP3A. A strong CYP3A inhibitor increased the AUC of olaparib by 2.7-fold, and PBPK modeling predicted that a moderate CYP3A inhibitor would likely increase olaparib AUC by 2-fold. Dose reductions to 150 mg twice daily are recommended for concomitant use of a strong CYP3A inhibitor and to 200 mg for concomitant use of a moderate CYP3A inhibitor. A strong CYP3A inducer decreased the AUC of olaparib by 87%, and PBPK modeling predicted that a moderate CYP3A inducer would likely decrease olaparib AUC by half. Concomitant use of a strong or moderate CYP3A inducer should be avoided. If a moderate CYP3A inducer must be coadministered, there is a potential for reduced efficacy.

FDA approval of olaparib was primarily based on an open-label, nonrandomized clinical trial in 298 patients with deleterious or suspected deleterious gBRCAm-associated cancer, including 193 patients with ovarian cancer (16). Patients were treated with olaparib capsules at a dose of 400 mg orally twice daily until disease progression or intolerance to therapy. Local test results for BRCA status were used to assess patient eligibility for the trial. Samples from a subset of enrolled patients from the intended population were retrospectively evaluated at one laboratory, Myriad Genetic Laboratories, Inc., using the BRACAnalysis CDx in a clinical bridging study.

Of the 193 patients in the ovarian cancer cohort, 137 patients had measurable disease at baseline and had received three or more prior lines of chemotherapy. The majority (94%) of these patients were white/Caucasian and had a baseline ECOG performance status of 0 or 1 (93%); the median age at enrollment was 58 years. The median number of prior chemotherapy regimens was five, and the maximum number of prior regimens was 14.

The primary endpoint was investigator-assessed tumor response rate by RECIST v.1.1 in all treated patients. Secondary objectives included objective response rate (ORR) in patients with measurable disease only and duration of response (DOR). A blinded independent radiologic review was not performed. The ORR was 34% [95% confidence interval (CI), 26–42] with a median DOR of 7.9 months (Table 1).

Of the 137 patients, specimens from 61 patients were available for retrospective testing with the BRACAnalysis CDx in the bridging study for clinical validation of the device. The concordance between the local test results, as reported in the Case Report Form, and the results from the BRACAnalysis CDx were 96.7% (59/61; 95% CI, 88.7–99.6). Among the discordant results, one sample did not yield a callable result with the BRACAnalysis CDx, and another sample had different classification results between the local test and the BRACAnalysis CDx (deleterious vs. variant of unknown significance, respectively), although the specific variant that was detected by both tests matched. The ORR for the 59 patients with confirmed gBRCA mutations was 41% (95% CI, 28–54), with a median DOR of 8.0 months.

The primary safety population included 223 patients from six studies, including patients with relapsed ovarian cancer with gBRCA mutation who had received three or more prior treatment regimens. The median exposure to olaparib in this population was 158 days. Dose interruptions were reported in 40% of these patients, and dose reductions were reported in 4%. Treatment discontinuations due to adverse drug reaction occurred in 7%. The most common adverse events leading to treatment discontinuation included nausea and vomiting, intestinal obstruction, anemia, and thrombocytopenia.

Eight patients (4%) had adverse reactions leading to death. The fatal adverse reactions included 2 patients with acute leukemia and 1 patient each with death attributed to chronic obstructive pulmonary disease, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture.

The most common (≥20%) grade 1–4 and grade 3–4 adverse reactions in patients receiving olaparib are shown in Table 2. Thirty-five percent of patients experienced one or more serious adverse events, and the most common of these events are shown in Table 3.

Myelodysplastic syndrome and acute leukemia are the most concerning adverse reactions associated with olaparib therapy. Six confirmed cases of MDS/AML occurred in the 298 patients (2%) enrolled in the single-arm study of olaparib monotherapy in patients with gBRCAm-associated ovarian cancer. In a randomized placebo controlled trial of olaparib maintenance monotherapy in platinum-sensitive ovarian cancer, MDS/AML occurred in 3 of the 136 patients treated with olaparib (2%) as compared with 1 of the 129 patients treated with placebo (0.8%). Among the 2,618 patients exposed to olaparib at the time of the FDA review, 22 cases of MDS/AML were reported (0.8%), with 17 cases resulting in death. The precise number of patients with gBRCAm status who have been exposed to olaparib is unknown, but the majority of cases occurred in patients with gBRCAm status (n = 17) and in patients who were currently being treated for ovarian cancer (n = 18). Of those patients with gBRCAm status, 6 patients with ovarian cancer had a prior history of breast cancer, and the 1 patient with breast cancer had a history of ovarian cancer. Further epidemiologic research is needed to understand the baseline risk of developing therapy-related MDS/AML in patients with gBRCAm status; however, given the mechanism of action and increased rates of MDS/AML seen in the randomized studies of olaparib, there exists a clear safety signal that olaparib may increase the risk of developing MDS/AML.

Olaparib is the first new molecular entity approved for the treatment of ovarian cancer since 1996. The long gap between approvals demonstrates the challenge of developing novel therapeutics in ovarian cancer, as standard therapeutic regimens for the first-line and platinum-sensitive settings have high antitumor activity with benefits in overall survival, making it difficult to use an “add-on” trial design in which a new drug is added to an existing regimen. In more refractory ovarian cancer settings, randomized trials are possible, but a convincing demonstration of efficacy in a more resistant population has been elusive. Bevacizumab was recently approved as a supplemental Biologic License Application for use in combination with chemotherapy for the treatment of patients with platinum-resistant ovarian cancer based on the results of a randomized trial demonstrating an improvement in progression-free survival (PFS), which marked the first approval in this setting for over 15 years (17).

On June 25, 2014, New Drug Application 206162 was brought to the FDA's Oncologic Drug Advisory Committee (ODAC) to discuss olaparib for the maintenance treatment of gBRCAm-associated ovarian cancer based on the results of Study 19, a randomized placebo controlled trial assessing PFS in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer in partial or complete response to their last platinum-containing regimen (18). The efficacy results were based primarily on the prespecified subgroup analysis of 96 patients with deleterious germline BRCA mutations who were mostly retrospectively identified (19). The committee was asked whether the efficacy results, namely a 7-month improvement in median PFS and an HR of 0.17, along with the safety data in the gBRCAm population, demonstrated a favorable risk–benefit profile of olaparib maintenance monotherapy in gBRCAm-associated ovarian cancer.

After a robust discussion, the committee voted 11–2 that the results from Study 19 do not support an accelerated approval for the proposed indication. Primary reasons for voting against approval included a lack of OS benefit for maintenance therapy; uninterpretable results due to lack of multiplicity adjustment; unreliable results due to loss of randomization and small sample size; toxicity of therapy and risk of MDS/AML for patients not otherwise undergoing treatment; and a potential to hinder accrual to the confirmatory study.

Following the ODAC meeting and in further discussion with the FDA, the applicant submitted additional information in support of the use of olaparib monotherapy in a more refractory and narrowly defined population of patients with gBRCAm-associated ovarian cancer treated with three or more lines of chemotherapy. The applicant has addressed the concerns raised by the ODAC, as the approved indication is not in a maintenance setting, and patients typically would be treated with chemotherapy at this time. Enrollment for a potential confirmatory trial discussed at ODAC, SOLO-2, is complete.

This approval is not restricted to either the platinum-sensitive or platinum-resistant disease setting. Many patients with gBRCAm-associated ovarian cancer may still be responsive to platinum-based therapy even after three prior lines of chemotherapy; however, it is estimated that treatment with olaparib would have a better response rate and favorable safety profile as compared with available single-agent chemotherapeutic options. Patients in this disease setting will most likely have cumulative toxicity and would benefit from a drug with demonstrable antitumor activity and a relatively mild safety profile. The tolerability profile of olaparib in this heavily pretreated population was an important factor in determining the overall benefit–risk assessment of olaparib therapy. The applicant is conducting a randomized trial (SOLO-3) directly comparing the safety and efficacy of olaparib monotherapy versus chemotherapy in the third-line ovarian cancer setting that also could be a potential confirmatory trial.

Overall, olaparib monotherapy represents a new treatment modality for patients with advanced, heavily pretreated gBRCAm-associated ovarian cancer; however, the clinical benefit must be confirmed in a randomized clinical trial. In addition, the risks of the development of MDS/AML must be further characterized, and this led to a post-marketing requirement (PMR) for annual reporting to the FDA of all cases of MDS/AML from ongoing clinical trials and spontaneous safety reports. Other PMRs included the assessment of olaparib in patients with renal impairment and with hepatic impairment.

Further information regarding the review of the application can be found at the Drugs@FDA website (20). Information about the device application can be found online at the FDA PMA database website (21).

No potential conflicts of interest were disclosed.

Conception and design: G. Kim, G. Ison, A.E. McKee, R. Sridhara, R. Pazdur

Development of methodology: G. Kim, A.E. McKee, R. Sridhara, L. Zhao

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): G. Kim, R. Venugopal

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): G. Kim, G. Ison, A.E. McKee, H. Zhang, S. Tang, T. Gwise, R. Sridhara, H.-J. Chiu, T. Palmby, A.M. Russell, E. Pfuma, H. Li, L. Zhao, Q. Liu, A. Ibrahim, R. Pazdur

Writing, review, and/or revision of the manuscript: G. Kim, G. Ison, A.E. McKee, H. Zhang, S. Tang, T. Gwise, R. Sridhara, E. Lee, A. Tzou, R. Philip, H.-J. Chiu, T.K. Ricks, T. Palmby, G. Ladouceur, E. Pfuma, H. Li, L. Zhao, Q. Liu, R. Venugopal, A. Ibrahim, R. Pazdur

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): G. Kim, G. Ison, A.E. McKee, R. Venugopal

Study supervision: R. Sridhara, R. Pazdur

Other (supervised the review of the application): A. Ibrahim