AstraZeneca and MSD’s Lynparza (olaparib) in combination with abiraterone and prednisolone has been approved in Japan for the treatment of adult patients with BRCA-mutated (BRCAm) castration-resistant prostate cancer with distant metastasis (mCRPC)….This approval by the Japanese Ministry of Health, Labour and Welfare was based on a subgroup analysis of the PROpel Phase III trial which showed that Lynparza plus abiraterone demonstrated highly clinically meaningful improvements in both radiographic progression-free survival (rPFS) and overall survival (OS) versus abiraterone alone in patients with BRCA mutations.

Health Canada has granted a Notice of Compliance with Conditions (NOC/c) for Lynparza® (olaparib) 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.

...Food and Drug Administration approved olaparib (Lynparza, AstraZeneca Pharmaceuticals LP) with abiraterone and prednisone (or prednisolone) for adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved companion diagnostic test.

AstraZeneca and MSD's Lynparza (olaparib) has been granted conditional approval in China to treat adult patients with germline or somatic BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following treatment that included a new hormonal agent (abiraterone, enzalutamide).

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:...the treatment of patients with BRCA gene-mutated (BRCAm) castrate-resistant prostate cancer with distant metastasis (mCRPC)...

Lynparza is indicated as monotherapy for the treatment of adult patients with metastatic castration-resistant prostate cancer and BRCA1/2-mutations (germline and/or somatic) who have progressed following prior therapy that included a new hormonal agent.

Health Canada approved Lynparza (olaparib), for the treatment of adult patients with deleterious or suspected deleterious germline and/or somatic BRCA or ATM-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with a new hormonal agent (NHA).

Prostate Cancer: Useful in certain circumstances…Olaparib/abiraterone for BRCA mutation (category 1)….

The deals negotiated by NHS England and company AstraZeneca have enabled NICE to recommend olaparib as a clinically and cost-effective option:….for adults with HER2-negative, high-risk early breast cancer who have inherited faults in their BRCA1 or BRCA2 genes, after surgery and chemotherapy...and for adults with previously treated hormone-relapsed metastatic prostate cancer who have the same BRCA mutations.

Olaparib is a treatment option for patients with mCRPC and a pathogenic mutaion (germline /somatic) in a homologous recombination repair gene (BRCA1, BRCA2, ATM, BADR1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D or RAD54L) who have been treated with androgen-receptor therapy.

In all subgroups assessed, olaparib improved outcomes versus abiraterone or enzalutamide for patients with mCRPC with BRCA alterations whose disease had progressed on previous NHA.

Pts with HRRm, including BRCAm, were balanced between treatment arms and rPFS favoured abi + ola for all biomarker subgroups, including pts with non-HRRm, HRRm and BRCAm status...Meaningful rPFS improvement of ≥5 months was observed with abi + ola vs abi + pbo in all assessed biomarker subgroups. Updated results show a continuing trend towards improved OS and support a superior clinical benefit with abi + ola vs abi + pbo as 1L therapy for pts with mCRPC.

….139 (76.8%) yielded a result and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib and 38 received control….rPFS was longer in the olaparib group versus control [median 7.4 vs. 3.5 months; hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.21–0.53; nominal P < 0.0001], which is consistent with Cohort A ITT population (HR, 0.34; 95% CI, 0.25–0.47).

Small subgroups limit interpretation for some genes. Olaparib antitumor activity is greatest in pts with BRCA alterations, with a spectrum of clinical sensitivity to olaparib as defined by rPFS and OS across the broader population with alterations in other HRR genes.

Exploratory analyses in pts with alterations in BRCA1 and/or BRCA2 (BRCA, regardless of co-occurring alterations with other HRR genes) or in single genes were conducted...Evidence of olaparib antitumor activity was observed in subgroups with >10 pts...Olaparib antitumor activity is greatest in pts with BRCA alterations, with a spectrum of clinical sensitivity to olaparib as defined by rPFS and OS across the broader population with alterations in other HRR genes.

...AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending LYNPARZA for approval as monotherapy for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1/2 mutations (germline and/or somatic) who have progressed following a prior therapy that included a new hormonal agent....The CHMP’s positive opinion was based on a subgroup analysis of patients with BRCA1/2 mutations from the Phase 3 PROfound trial.

Cohort A included 245 patients with at least one alteration in BRCA1, BRCA2, or ATM,...The median duration of overall survival in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (hazard ratio for death, 0.69; 95% confidence interval [CI], 0.50 to 0.97; P=0.02)....Among men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration in BRCA1, BRCA2, or ATM and whose disease had progressed during previous treatment with a next-generation hormonal agent, those who were initially assigned to receive olaparib had a significantly longer duration of overall survival than those who were assigned to receive enzalutamide or abiraterone plus prednisone as the control therapy, despite substantial crossover from control therapy to olaparib.

At data cut-off (20 March 2020), median final OS in Cohort A was significantly longer with olaparib than with physician’s choice of enzalutamide or abiraterone (HR 0.69; 95% CI 0.50, 0.97; P=0.0175),...Despite extensive crossover from the control arm, olaparib conferred a statistically significant and clinically meaningful prolongation of OS vs sequential therapy with enzalutamide or abiraterone in men with mCRPC with progression on prior therapy and alterations in BRCA1, BRCA2 or ATM, with a 31% reduction in the risk for death.

Cohort A (245 patients) had at least one alteration in BRCA1, BRCA2, or ATM...In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001)...

Subgroup analyses of rPFS and overall survival (OS) favored ola vs pcNHA irrespective of prior taxane in Cohort A, Cohorts A+B and pts with a BRCA1 and/or BRCA2 or CDK12 alteration (Table). In the ATM subgroup hazard ratio (HR) point estimates for rPFS and OS were lower in pts who had received prior taxane vs pts who had not, but 95% CIs overlapped and pt numbers were small so data should be interpreted with caution.

AstraZeneca today announced that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy designation (BTD) for the oral poly ADP-ribose polymerase (PARP) inhibitor Lynparza (olaparib), for the monotherapy treatment of BRCA1/2 or ATM gene mutated metastatic Castration Resistant Prostate Cancer (mCRPC)...

...pts with alterations in BRCA1, BRCA2 or ATM...Pts were randomized (2:1) to ola (300 mg bid)...pts with mCRPC and HRR alterations with prior NHA treatment, ola improved rPFS and ORR vs pcNHA, with a favorable trend for OS despite crossover. Safety was generally consistent with the known profile of ola.

...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. ...

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

...Time from randomisation to second progression or clinical progression or death`To assess progression in pain severity domain, change in pain interference domain, and pain palliation`Functional Assessment of Cancer Therapy- Prostate Cancer (FACT-P) total score, Functional Assessment of Cancer Therapy- General (FACT-G) total score, trial outcome index, functional well-being, physical well-being, prostate cancer subscale, and Functional Assessment of Cancer Therapy (FACT) Advanced Prostate Symptom Index-6 (FAPSI-6)`Tumour and blood samples for mutations in Breast Cancer 1 gene (BRCA1), or Breast Cancer 2 gene (BRCA2), Ataxia-telangiectasia mutated (ATM) and 12 other Homologous Recombination Repair (HRR) genes will be evaluated.`...

...(The presence of a loss-of-function germline mutation in the BRCA1 and/or BRCA2 gene must be confirmed prior to consent according to local practice)....

...Time from randomisation to second progression or clinical progression or death, whichever occurs earlier`To assess progression in pain severity domain, change in pain interference domain, and pain palliation`Functional Assessment of Cancer Therapy- Prostate Cancer (FACT-P) total score, Functional Assessment of Cancer Therapy- General (FACT-G) total score, trial outcome index, functional well-being, physical well-being, prostate cancer subscale, and Functional Assessment of Cancer Therapy (FACT) Advanced Prostate Symptom Index-6 (FAPSI-6)`Tumour samples for mutations in Breast Cancer 1 gene (BRCA1), or Breast Cancer 2 gene (BRCA2), Ataxia-telangiectasia mutated (ATM) and 12 other Homologous Recombination Repair (HRR) genes will be evaluated.`...

...Deleterious or suspected deleterious BRCA1/2 mutation in tumor tissue....

...Histologically proven advanced cancer, either locally or metastatic, harboring a specific pathogenic genetic alteration (with the exception of breast, pancreas, or prostate cancer patients harboring a BRCA1/2 mutation and HRD ovarian cancer) 4....

...For enrichment stage of trial only (if necessary): Confirmation of a suspected/known deleterious mutation in a gene of interest (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or other DNA repair genes) via CLIA certified testing....

In this exploratory analysis, 1L mCRPC treatment with abi and ola resulted in higher PSA response rates and prolonged time to PSA progression vs abi and pbo in all pts, with more pronounced improvements in the HRRm and BRCAm subgroups.

Thirty patients with mCRPC with BRCA1/2 mutations were treated with olaparib. The disease control rate was 69% (95% CI, 51 to 81), and the objective response rate was 58% (95% CI, 37 to 77). The median radiographic progression-free survival and the median overall survival were 38.4 (95% CI, 16.3 to 52.1) weeks and 76.4 (95% CI, 49.3 to 106.0) weeks, respectively.

Sensitivity analysis of rPFS by blinded independent central review was consistent. At DCO2 (14/03/22) rPFS was consistent with the primary analysis (25.0 vs 16.4 months; HR 0.67, 95% CI 0.56–0.81). A trend towards improved OS with abi + ola vs abi + pbo continued (maturity 40%; HR 0.83; 95% CI 0.66–1.03). Safety and tolerability results remained stable.Meaningful rPFS improvement of ≥5 months was observed with abi + ola vs abi + pbo in all assessed biomarker subgroups. Updated results show a continuing trend towards improved OS and support a superior clinical benefit with abi + ola vs abi + pbo as 1L therapy for pts with mCRPC.

≥50% PSA decline was 79%, 67%, and 85% of pts in Arms 1, 2, and 3, respectively. Median PSA nadir (ng/mL) (95% CI) Arms 1-3: 2.17 (0.44, 49.27), 3.10 (0.83, 12.01), and 0.50 (0.10, 2.13), respectively. In mCRPC pts with inactivating BRCA1, BRCA2 and/or ATM alterations Abi/pred + olaparib was well tolerated and resulted in longer PFS and better PSA response vs either agent alone.

In patients with at least one alteration in BRCA1, BRCA2, or ATM (Cohort A), the primary endpoint of PFS was significantly longer for the olaparib group (7.4 months) than the control group (3.6 months) with HR = 0.34, 95% CI, 0.25–0.47; p < .001.

Nine pts with OR and 8 with SD16+ were observed for DC and OR rates of 68% (90% CI: 53% - 77%) and 36% (95% CI: 18% - 57%), respectively.

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.

Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%)...Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate.

Patients with BRCA1/2 mutations had median PFS of 12.3 mo versus 2.4 mo for those with ATM mutations...Men with mCRPC harboring ATM mutations experienced inferior outcomes to PARP inhibitor therapy compared to those harboring BRCA1/2 mutations.