Recommendations...Poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in BRCA1/2 carriers.

While olaparib and talazoparib are FDA indicated in HER2-negative disease, the panel supports use in any breast cancer subtype associated with a germline BRCA1 or BRCA2 mutation.

IDFS and DDFS were sustained with similar effect size: IDFS HR 0.63 (95% CI 0.50, 0.78), 4-yr IDFS 82.7% vs 75.4% (diff. 7.3%; 95% CI 3.0%, 11.5%). DDFS HR 0.61; 95% CI 0.48, 0.77); 4-yr DDFS 86.5% vs 79.1% (diff. 7.4%; 95% CI 3.6%, 11.3%)….In pts with gBRCAm and high-risk HER2-negative EBC after [N]ACT, at 3.5 years MFU, adjuvant olaparib significantly improved OS, as well as IDFS and DDFS...

In olaparib (ola) pts with a BRCAm, ORR was 60% (6/10) and 57% (37/65) in pts with HRD score <42 and ≥42, respectively...BRCA2; PFS was 8.2 months for ola and BRCA1; PFS was 6.5 months for ola...

AstraZeneca and MSD’s Lynparza (olaparib) has been approved in Japan for the treatment of advanced ovarian, prostate and pancreatic cancers….The three approvals authorise Lynparza for:...maintenance treatment after platinum-based chemotherapy for patients with BRCAm curatively unresectable pancreas cancer.

...b) Male or female with histologically confirmed, metastatic breast cancer and documented BRCA1 or BRCA2 germline mutation, regardless of tumour steroid hormone receptor or HER-2 status OR...

...Histologically confirmed recurrent and metastatic TNBC patients without BRCA1/2 mutation and BRCA1 promoter methylation....

...- For participants who have non-breast or -ovarian cancers that are breast cancer susceptibility gene 1/2 (BRCA1/2) mutated (BRCAm), or who have cancers that are BRCA1/2 non-mutated and homologous recombination repair nonmutated:...

...- Documented BRCA mutations (germline and/or somatic mutation in BRCA1 (Breast Cancer gene 1) and/or BRCA2 (Breast Cancer gene 2) that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function))...

...Cohort 1: Documented germline or somatic mutation in BRCA1, BRCA2, PALB2, RAD51C or RAD51D that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function)....

...Absence of deleterious or suspected deleterious germline mutations in BRCA1 and BRCA2....

...Patients are eligible to undergo BRCA testing even if they have - Documented germline mutation in Breast Cancer susceptibility genes: BRCA1 and/or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function) - At least one lesion that can be accurately assessed at baseline by CT/MRI and is suitable for repeated assessment. ...

...Assess the efficacy of olaparib in HER2-negative early Breast Cancer and HRD (BRCA 1/2 mutations and/or HRD positive). ...

...Men with BRCA1/2 mutation and metastatic breast cancer will be eligible for study....

...For patients enrolling in the sporadic serous epithelial ovarian cancer group, Group B, a negative family history (BRCAPRO score less than or equal to 20% or negative BRCA1/2 mutation test)....

...- Documented germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious...

...Mutation of BRCA 1 and/or 2 for ARM B only...

...Los pacientes deben ser hombres o mujeres de ≥18 años 3.Los pacientes deben de tener la capacidad de proporcionar un formulario de consentimiento informado por escrito firmado y fechado antes de cualquier procedimiento, muestreo y análisis.4.Cáncer de mama confirmado histológica o citológicamente con evidencia de enfermedad localmente avanzada5.Los pacientes pueden tener cáncer de mama triple negativo y HER2 negativo o cáncer de mama ER / PgR positivo, siempre que sean HER2 negativo y coherentes con los estándares locales y las pautas más recientes de ASCO CAP Cohorte 1: Mutación en BRCA1, BRCA2, PALB2, RAD51C o RAD51D 6.Pacientes que hayan recibido platino y no haya habido evidencia de progresión de la enfermedad durante la quimioterapia.7.Pacientes que hayan recibido platino y / o inhibidores de PARP y que hayan transcurrido al menos 6 meses entre la última dosis de PARP. ...

...1- Provision of informed consent prior to any study specific procedures 2- Female or male aged > 18 years 3- Histologically proven advanced cancer, either locally or metastatic, harboring a specific pathogenic genetic alteration (with the exception of breast, pancreas, ovarian or prostate cancer patients harboring a BRCA1/2 mutation) 4- No approved targeted therapy for the specific genetic alteration in the specific tumor type 5- No other genomic driven phase I, II or III trial available for the specific genomic alteration in the specific tumor type 6- Available tumor tissue for verification of the mutation by Sanger sequencing. ...

...Germline and somatic BRCA status (genetic testing) are planned for future correlative evaluation, in order to examine treatment and circulating tumor deoxyribonucleic acid (ctDNA) response as stratified by BRCA 1/2 mutational status....

...- All participants must have documented BRCA 1/2 mutant or other HRD+ in solid tumor, which is identified through a validated sequencing test...

...- Germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious....

...- Documented somatic mutation (deleterious or suspected deleterious) in BRCA1 or BRCA2 through any CLIA approved lab only if in addition to the lack of a germline BRCA1/2 mutation is demonstrated through a CLIA approved lab....

...- Documented germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function)....

In this retrospective, single institution study, patients who were treated with off-label, off-protocol olaparib for metastatic breast cancer harboring sBRCA1/2 or germline or somatic non-BRCA1/2, HRR mutations were identified.....The median progression free survival in patients with a sBRCA1/2 mutation was 6.5 months (range 5-9 months) vs. 3 months (range 2-4 months) in patients with non-BRCA1/2, HRR mutations....This single institution experience adds to recent larger reports confirming evidence for PARPi therapy in patients with metastatic breast cancer harboring sBRCA1/2 mutations.

Nine different cancer types were included: prostate (n=11), breast (n=4), ovarian (n=2), pancreatic (n=3), colorectal (n=2), biliary tract (n=2), kidney (n=1), adrenal gland (n=1) and endometrial (n=1). The primary endpoint was clinical benefit (CB: objective response or stable disease (SD) ≥ 16 weeks). CB was observed in pts with both somatic and germline BRCA alterations and across tumor types.

Patients received olaparib 300 mg...Responses were gene specific (Table): gPALB2 and sBRCA mutations predicted response…

Patients received olaparib 300 mg orally twice a day until progression….In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with gPALB2 (ORR, 82%) and sBRCA1/2 (ORR, 50%) mutations....PARP inhibition is an effective treatment for patients with MBC and gPALB2 or sBRCA1/2 mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond gBRCA1/2 mutation carriers.

The patient is a 67-year-old woman who underwent surgery for left breast cancer in 1990 and right breast cancer in 2003....BRCA1/2 analysis showed BRCA1 mutation, so olaparib was started in 2020. The metastatic lesions were reduced markedly, and the skin metastases were crusted over.

A 43 -year-old woman presented to the hospital with a right breast tumor...this showed a result positive for a deleterious mutation in BRCA1. Metastatic lesions, including barky growth, in the liver metastasis were well controlled, as confirmed by CT imaging 4 months after the start of olaparib.

Here, we investigated the ability of paraspeckle component 1 (PSPC1), as an additional synthetic lethal partner with BRCA1/2, to enhance olaparib sensitivity in preclinical models of BRCA1/2-mutated breast and ovarian cancers. In vitro, the combined olaparib and PSPC1 small interfering RNA (siRNA) exhibited synergistic anti-proliferative activity in BRCA1/2-mutated breast and ovarian cancer cells. The combination therapy also demonstrated synergistic tumor inhibition in a xenograft mouse model.

Two BRCA-proficient BC cell lines, MDA-MB-231 and T47D BC, were used….MDA-MB-231 cells exhibited a higher dose enhancement factor for Olaparib than T47D cells. Olaparib increased radiation-induced G2/M cell cycle arrest and apoptosis specifically in MDA-MB-231 cells....This study found that Olaparib enhanced radiation efficacy in BRCA-proficient breast cancer cells...

The effect of the PARP inhibitor olaparib was assessed in vitro, using cultured circulating tumor cells (CTCs) from a patient with a somatically acquired BRCA1 mutation and a second patient with an acquired BRCA2 mutation. Functional analysis of a CTC culture harboring a somatic BRCA1-mutation demonstrated high sensitivity to PARP inhibition, while another CTC culture harboring a somatic BRCA2 mutation showed no differential sensitivity.

The growth inhibition effect of AZD2281 was significantly higher in the BRCA wild-type cell lines with BRCA1 allelic loss than in the BRCA wild-type cell line without BRCA1 allelic loss (Fig. 1a).