Regulatory Decision Summary for Lynparza

The purpose of this Supplement to a New Drug Submission (SNDS) was to seek market authorization for the use of Lynparza in combination with abiraterone plus prednisone or prednisolone for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC).

After review, a notice with compliance with conditions (NOC/c) was recommended and the indication was revised to:

“Lynparza is indicated in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious germline and/or somatic BRCA mutated metastatic castration resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated. BRCA mutation must be confirmed before Lynparza treatment is initiated”.

The PROpel study, a randomized, double-blind, placebo-controlled, multicentre Phase III study of olaparib plus abiraterone relative to placebo plus abiraterone as first-line therapy in men with metastatic castration-resistant prostate cancer (mCRPC) was conducted in support of the proposed indication (Lynparza in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC)). The sponsor referred to non-clinical studies as well as to the phase II study D081DC00008 (Study 8) to support the use of the olaparib + abiraterone (ola+abi) combination for unselected patients (all-comers) with mCRPC in the pivotal PROpel study. The primary endpoint of the study was radiographic progression-free survival (rPFS). Key secondary endpoint was overall survival (OS).

The study met its primary objective for the all-comers. However, because the subpopulation of mCRPC patients with a mutation in the homologous recombination DNA repair [HRRm] pathway are known to be specifically responsive to olaparib, there was a possibility for that subpopulation of patients to drive the overall study response. Subgroup analyses showed that HRRm patients (rPFS HRRm HR = 0.44 [95% CI 0.26, 0.74] HRR status determined using tissue biopsy) were more responsive to the combination than non-HRRm patients (rPFS non-HRRm HR = 0.81 [95% CI 0.62, 1.07]). OS data for non-HRRm patients was either weakly favorable (HR = 0.87 [95% CI 0.64, 1.19]) or detrimental (HR = 1.10 [95% CI 0.77, 1.57]) to the drug combination depending on the way HRRm status was determined (using circulating tumour DNA or tissue from biopsy).

A post hoc analysis was conducted using the HRRm subgroup to examine the rPFS and OS data for HRRm-BRCA and for HRRm-Non BRCA mutations. The results from the HRRm-BRCA subgroup (N = 47 ola+abi vs 38 pla+abi) were as follow; rPFS HR 0.23 (CI 95% 0.12, 0.43) and OS HR 0.39 (CI 95% 0.17, 0.87) ; OS data not mature. Results from the HRRm-Non BRCA subgroup (N = 64 ola+abi vs 77 pla+abi) were as follow; rPFS HR 0.80 (CI 95% 0.50, 1.27) and OS HR 1.30 (CI 95% 0.68, 2.48); OS data are not mature. These results strongly supported the hypothesis that the overall response observed with the all-comer population was driven by the HRRm-BRCA subpopulation of patients.

The most common adverse events (AEs) reported in the ola+abi arm (frequency ≥ 5% of patients) were anaemia (45.5%), nausea (28.1%), fatigue (27.9%), constipation (17.3%), diarrhea (17.3%) and vomiting (13.1%).

Adverse events leading to death were reported in 16 patients (4.0%) in the ola+abi arm and 17 patients (4.3%) in the pla+abi arm. AE leading to death in the ola+abi group include COVID-19 (7), pneumonia (4), pulmonary embolism (1), mitral valve disease (1), myocardial ischemia (1), sudden death (1), subdural haematoma (1), craniocerebral injury (1), and general physical health deterioration (1). None were considered treatment related by the investigator.

Grade 3 or 4 AE preferred terms for which the incidence differed by > 2% between treatment groups were anaemia (ola+abi: 15.1 %, pla+abi: 3.3%) and pulmonary embolism (6.5%, 1.8%).

Serious AEs (SAEs) were reported in 135 patients (33.9%) on the ola+abi arm compared to 107 patients (27.0%) on the pla+abi arm. Anaemia was the most common SAE on the ola+abi arm with 5.8% of patients. Pulmonary embolism was reported in 3.3% of patients on ola+abi; COVID-19 was reported as an SAE in 3.0% of patients and 2.3% of patients in the ola+abi and pla+abi arms, respectively.

Incidence of venous thromboembolic events (VTE) including pulmonary embolism was updated in the product monograph, section 7 “Warnings & Precautions” and in section “8 Adverse Reactions/Clinical trials Adverse Reactions” to reflect the reporting of pulmonary embolism observed during PROpel trial. The safety profile derived from the PROpel study for olaparib in combination with abiraterone was consistent with the safety profile reported for olaparib used alone and is considered acceptable.

PARP inhibitors (PARP-I) have been shown to be particularly efficient at targeting cancer cells with deficiencies in the DNA repair pathways (Homologous Recombination Repair-HRR pathway) particularly mutations to the BRCA 1 and BRCA-2 genes, not at targeting cancer cells that are HRR wild-type. Although nonclinical studies supported the hypothesis that ola+abi affected the growth of prostate cancer cells independently of the HRR gene mutation status, the hypothesis had not been validated in the context of a clinical trial. The design of the PROpel study as well as of Study 8 did not address the question as to whether non-HRRm patients derived a benefit from the combination ola-abi (no dedicated cohort of patients for HRRm and non-HRRm patients).

Results from the post hoc subgroup analysis of the HRRm-BRCA and HRRm-non BRCA study participants were considered to revise the adjust the indication of the combination ola+abi, although there were limitations associated with these data, such as absence of stratification for the HRRm status and the fact that PROpel was not designed and powered to assess efficacy within individual HRRm mutations. However, the efficacy of olaparib at targeting cancer cells with deficiencies in the BRCA 1/2 genes is well documented.

In summary, the PROpel study was not designed to validate the hypothesis as to whether the non HRRm patient population included in this trial derived a benefit from the treatment with the combination ola+abi. A Post hoc analysis of the HRRm subgroup of patients showed that patients with a mutated BRCA 1 or 2 genes were driving the response to the combination ola+abi. Therefore, the proposed indication was modified to reflect these observations and to more accurately target the population of patients that would benefit from this treatment. The recommended indication also excludes patients for whom chemotherapy is indicated to reflect the population of patients enrolled into the PROpel study. A NOC with conditions is recommended, pending the confirmation of the clinical benefit in the BRCA mutant subgroup from the final efficacy analysis of the PROpel study. The analyses should verify and describe the clinical benefit of olaparib plus abiraterone acetate and prednisone in terms of Overall Survival in the BRCA subgroup.

The response to the Qualifying Notice (QN) submitted by the sponsor and the Letter of Undertaking (LoU) are deemed acceptable.