외국의 약물유전정보

1 INDICATIONS AND USAGE

1.1 First-Line Maintenance Treatment of BRCA-mutated Advanced Ovarian Cancer

Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1)].

1.2 First-line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab

Lynparza is indicated in combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either:

• a deleterious or suspected deleterious BRCA mutation, and/or

• genomic instability.

Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1)]

1.4 Advanced Germline BRCA-mutated Ovarian Cancer After 3 or More Lines of Chemotherapy

Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1)].

1.5 Germline BRCA-mutated HER2-negative Metastatic Breast Cancer

Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer, who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza.

1.6 First-Line Maintenance Treatment of Germline BRCA-mutated Metastatic Pancreatic Adenocarcinoma

Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza.

1.7 HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer

Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1)].

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Information on FDA-approved tests for the detection of genetic mutations is available at http://www.fda.gov/companiondiagnostics.

Select patients for treatment with Lynparza based on the presence of deleterious or suspected deleterious HRR gene mutations, including BRCA mutations, or genomic instability based on the indication, biomarker, and sample type (Table 1).

Table 1 Biomarker Testing for Patient Selection

* Where testing fails or tissue sample is unavailable/insufficient, or when germline testing is negative, consider using an alternative test.

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

Germline BRCA-mutated HER2-negative Metastatic Breast Cancer

OlympiAD

The safety of Lynparza was evaluated in gBRCAm patients with HER2-negative metastatic breast cancer who had previously received up to two lines of chemotherapy for the treatment of metastatic disease in OlympiAD [see Clinical Studies (14.5)]. Patients received either Lynparza tablets 300 mg orally twice daily (n=205) or a chemotherapy (capecitabine, eribulin, or vinorelbine) of the healthcare provider’s choice (n=91) until disease progression or unacceptable toxicity. The median duration of study treatment was 8.2 months in patients who received Lynparza and 3.4 months in patients who received chemotherapy.

Among patients who received Lynparza

HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer

PROfound

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular functions, such as DNA transcription and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer, both as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA1/2, ATM, or other genes involved in the homologous recombination repair (HRR) of DNA damage and correlated with platinum response. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

14 CLINICAL STUDIES

14.7 HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer

HRR pathway (BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L) were randomized in Cohort B; patients with co-mutations (BRCA1, BRCA2, or ATM plus a Cohort B gene) were assigned to Cohort A. Although patients with PPP2R2A gene mutations were enrolled in the trial, Lynparza is not indicated for the treatment of patients with this gene mutation due to unfavorable risk-benefit.

Patients with HRR gene mutations were identified by tissue-based testing using the Foundation Medicine FoundationOne® clinical trial HRR assay performed at a central laboratory.

Determination of deleterious or suspected deleterious somatic or germline HRR mutation status in line with the FDA approved mutation classification and testing criteria for the Foundation Medicine F1CDx tissue-based assay and assessment of the germline-BRCA status using the Myriad BRACAnalysis CDx blood-based assay was performed retrospectively. Representation of individual gene mutations by cohort is provided in Table 25. No patients were enrolled who had mutations in two of the 15 pre-specified HRR genes: FANCL and RAD51C.

Table 25 Frequency of Patients with HRR Mutations Enrolled in PROfound

# Lynparza is not indicated for patients with PPP2R2A mutations.

Although 10 patients with PPP2R2A mutation were included in all analyses of Cohort A+B, Lynparza is not indicated for this population due to unfavorable risk-benefit. 

(2022.12.16 업데이트)