On November 5, 2020 Veracyte, Inc. (Nasdaq: VCYT), a pioneering genomic diagnostics company, reported that the Federal Joint Committee (G-BA) has approved its Prosigna Breast Cancer Gene Signature Assay (Press release, Veracyte, NOV 5, 2020, View Source [SID1234570040]). The G-BA decision to reimburse the Prosigna test will provide access to the test for all breast cancer patients in Germany with HR+/HER2- early-stage breast cancer.

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The Prosigna Assay is a second-generation breast cancer test, meaning that it uses advanced genomic technology combined with clinical and pathologic features to inform next steps for patients with early-stage breast cancer. The test analyzes the activity of 50 genes known as the PAM50 gene signature, along with tumor size, lymph node involvement, and a tumor proliferation score to provide early-stage breast cancer patients and their physicians with a prognostic score indicating the probability of cancer recurrence during the next 10 years.

"We are pleased with the G-BA decision, which will enable more breast cancer patients and their physicians in Germany to benefit from the genomic insights offered by our Prosigna test," said Bonnie Anderson, chairman and chief executive officer of Veracyte. "Further, because Prosigna is performed by laboratories locally, this decision will enable German laboratories to deliver precision medicine solutions directly to their physician customers."

The Prosigna test is recommended in guidelines from the German Association of Gynecologic Oncology (AGO), as well as the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper), the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and the National Institute for Health and Care Excellence (NICE) in the United Kingdom.

Every year around 70,000 women in Germany develop early breast cancer. In many cases, a clear therapy recommendation for or against adjuvant chemotherapy is challenging based on the clinicopathological criteria alone. The Federal Joint Committee supports the use of biomarkers, now including Prosigna, to inform treatment decisions based upon the patient’s individual cancer recurrence risk.

About Prosigna

Prosigna is a prognostic Breast Cancer Gene Signature assay indicated in female breast cancer patients who have undergone either mastectomy or breast-conserving therapy in conjunction with locoregional treatment consistent with standard of care, either as a prognostic indicator for distant recurrence-free survival at 10 years in post-menopausal women with Hormone Receptor- Positive (HR+), lymph node-negative, Stage I or II breast cancer or lymph node-positive (1–3 positive nodes, or 4 or more positive nodes), Stage II or IIIA breast cancer to be treated with adjuvant endocrine therapy alone, when used in conjunction with other clinicopathological factors.

In addition to the risk of recurrence (ROR) information, in Europe the assay provides the intrinsic subtypes of the tumor tissue within three groups – low, intermediate and high. The test’s performance is validated for use on the nCounter Analysis System in laboratories across Europe.

On November 5, 2020 AstraZeneca and MSD’s Lynparza (olaparib) has been approved in the European Union (EU) for the 1st-line maintenance treatment with bevacizumab of patients with homologous recombination deficient (HRD)-positive advanced ovarian cancer (Press release, AstraZeneca, NOV 5, 2020, View Source [SID1234570039]).

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Ovarian cancer is the fifth most common cause of cancer death in the EU and the five-year survival rate is approximately 45%, due partly because women are often diagnosed with advanced disease (Stage III or IV).1-3

The approval by the European Commission was based on a biomarker subgroup analysis of the PAOLA-1 Phase III trial which showed Lynparza, in combination with bevacizumab maintenance treatment, demonstrated a substantial progression-free survival (PFS) improvement versus bevacizumab alone for patients with HRD-positive advanced ovarian cancer. It follows the recommendation for approval by the Committee for Medicinal Products for Human Use of the European Medicines Agency in September 2020.

Isabelle Ray-Coquard, principal investigator of the PAOLA-1 Phase III trial and medical oncologist, Centre Léon Bérard and President of the GINECO group, Paris, France, said: "For women with advanced ovarian cancer, the goal of 1st-line treatment is to delay disease progression for as long as possible with the intent of achieving long-term remission. Unfortunately, once a patient’s cancer recurs, it historically has been incurable. Lynparza together with bevacizumab has demonstrated an impressive median progression-free survival benefit of more than three years and is poised to become the standard of care for eligible patients with HRD-positive tumours in the EU."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: "Half of all newly diagnosed patients with advanced ovarian cancer have HRD-positive tumours. Women treated with Lynparza in combination with bevacizumab in the PAOLA-1 Phase III trial lived progression free for a median of more than three years, showing that HRD testing should be an essential component of clinical diagnosis. HRD status can help physicians select a personalised 1st-line treatment regimen for patients to substantially delay relapse in this devastating disease."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "Biomarker testing has rapidly enhanced our understanding of how PARP inhibition can help target this disease. The EU approval reinforces that HRD-positive tumours represent a distinct subset of advanced ovarian cancer and HRD testing is critical for women in this setting."

The PAOLA-1 Phase III trial showed that Lynparza, in combination with bevacizumab maintenance treatment, reduced the risk of disease progression or death by 67% (based on a hazard ratio of 0.33; 95% confidence interval 0.25-0.45). The addition of Lynparza improved PFS to a median of 37.2 months versus 17.7 with bevacizumab alone in patients with HRD-positive advanced ovarian cancer. The data from the PAOLA-1 trial was published in The New England Journal of Medicine in 2019.

Further results recently presented at the European Society for Medical Oncology Virtual Congress 2020 showed a statistically significant improvement in the key secondary endpoint of the time to second disease progression (PFS2). Lynparza with bevacizumab provided benefit beyond first disease progression, improving PFS2 to a median of 50.3 months versus 35.3 with bevacizumab alone.

The full EU indication is for Lynparza in combination with bevacizumab for the maintenance treatment of adult patients with advanced (FIGO Stages III and IV) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of 1st-line platinum-based chemotherapy in combination with bevacizumab and whose cancer is associated with HRD positive status defined by either a breast cancer susceptibility gene 1/2 (BRCA1/2) mutation and/or genomic instability.

Lynparza in combination with bevacizumab is approved in the US and in several other countries as a 1st-line maintenance treatment for patients with HRD-positive advanced ovarian cancer and is currently under regulatory review in other countries around the world.

Financial considerations

Following this approval for Lynparza in the EU, AstraZeneca will receive a regulatory milestone payment from MSD of $25m, anticipated to be booked as collaboration revenue during the fourth quarter of 2020.

Ovarian cancer

In 2018, there were nearly 68,000 new cases of ovarian cancer diagnosed in the EU and around 45,000 deaths.3 Approximately 50% of ovarian cancers are HRD-positive including BRCA1/2 mutation.4,5 Approximately 15% of ovarian cancers have a BRCA1/2 mutation.6 The primary aim of 1st-line treatment is to delay disease progression for as long as possible with the intent to achieve long-term remission.7-9

Homologous recombination deficiency

HRD, which defines a subgroup of ovarian cancer, encompasses a wide range of genetic abnormalities, including BRCA mutations and beyond. As with BRCA gene mutations, HRD interferes with normal cell DNA repair mechanisms and confers sensitivity to PARP inhibitors including Lynparza.10

PAOLA-1

PAOLA-1 is a double-blinded Phase III trial testing the efficacy and safety of Lynparza added to standard-of-care bevacizumab versus bevacizumab alone, as a 1st-line maintenance treatment for newly diagnosed advanced FIGO Stage III-IV high-grade serous or endometroid ovarian, fallopian tube, or peritoneal cancer patients who had a complete or partial response to 1st-line treatment with platinum-based chemotherapy and bevacizumab. AstraZeneca and MSD announced in August 2019 that the trial met its primary endpoint of PFS in the overall trial population.

Lynparza

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR pathway.

Lynparza is currently approved in a number of countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer. It is approved in the US, the EU, Japan, China, and several other countries as 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in the US as a 1st-line maintenance treatment with bevacizumab for patients with HRD-positive advanced ovarian cancer (BRCAm and/or genomic instability). Lynparza is approved in the US, Japan, and a number of other countries for germline BRCA-mutated, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer. It is also approved in the US, the EU and several other countries for the treatment of germline BRCAm metastatic pancreatic cancer. Lynparza is approved in the US for homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (BRCAm and other HRR gene mutations). Regulatory reviews are underway in several countries for ovarian, breast, pancreatic and prostate cancers.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 30,000 patients worldwide. Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

The AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and Koselugo (selumetinib), a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On November 5, 2020 AstraZeneca and MSD’s Lynparza (olaparib) reported that it has been approved in the European Union (EU) for patients with metastatic castration-resistant prostate cancer (mCRPC) with breast cancer susceptibility gene 1/2 (BRCA1/2) mutations, a subpopulation of homologous recombination repair (HRR) gene mutations (Press release, AstraZeneca, NOV 5, 2020, View Source [SID1234570038]).

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Prostate cancer is the second-most common type of cancer in men, with an estimated 1.3 million patients diagnosed worldwide in 2018.1 Approximately 12% of men with mCRPC have a BRCA mutation.2

The approval by the European Commission was based on a subgroup analysis of the PROfound Phase III trial which showed Lynparza demonstrated a substantial improvement in radiographic progression-free survival (rPFS) and overall survival (OS) versus enzalutamide or abiraterone in men with BRCA1/2 mutations.

Lynparza is the first and only PARP inhibitor approved in the EU in biomarker-selected advanced prostate cancer. It follows the recommendation for approval by the Committee for Medicinal Products for Human Use of the European Medicines Agency in September 2020.

Johann de Bono, one of the principal investigators of the PROfound Phase III trial, Head of Drug Development at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, said: "This approval in the EU is a landmark moment that begins a new era of precision medicine in prostate cancer. Lynparza now provides a targeted treatment option at a molecular level to patients with advanced prostate cancer who have historically poor prognosis and few treatment options."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: "Lynparza more than tripled radiographic progression-free survival and is the only PARP inhibitor to show an overall survival benefit versus certain new hormonal agents for men with BRCA-mutated metastatic castration-resistant prostate cancer. This approval means BRCA testing should now become a critical step in the diagnosis and determination of treatment for men with advanced prostate cancer in the EU."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "The PROfound Phase III trial showed Lynparza provided a clinical benefit for men living with BRCA1/2-mutated metastatic castration-resistant prostate cancer, offering an important option to improve overall survival for these patients in the EU. MSD, along with our collaborator AstraZeneca, looks forward to making this targeted treatment available for patients across the EU as quickly as possible."

The subgroup analysis from the PROfound Phase III trial showed Lynparza reduced the risk of disease progression or death by 78% (based on a hazard ratio [HR] of 0.22, 95% confidence interval [CI], 0.15-0.32; nominal p<0.0001) and improved rPFS to a median of 9.8 months versus 3.0 with enzalutamide or abiraterone in men with mCRPC with BRCA1/2 mutations. Lynparza reduced the risk of death by 37% (based on a HR of 0.63, 95% CI 0.42-0.95) with median OS of 20.1 months versus 14.4 with enzalutamide or abiraterone.

The primary results and overall survival results from the PROfound Phase III trial were published in The New England Journal of Medicine earlier this year.

The full EU approved indication for Lynparza is for the treatment of adult patients with mCRPC and BRCA1/2 mutations (germline and/or somatic) who have progressed following prior therapy that included a new hormonal agent.

Lynparza was approved in the US for men with HRR gene-mutated mCRPC in May 2020 based on the PROfound Phase III trial. Regulatory reviews are ongoing in other countries around the world.

AstraZeneca and MSD are exploring additional trials in metastatic prostate cancer including the ongoing PROpel Phase III trial testing Lynparza as a 1st-line treatment for patients with mCRPC in combination with abiraterone versus abiraterone alone. Data are anticipated in the second half of 2021.

Metastatic castration-resistant prostate cancer

Prostate cancer is associated with a significant mortality rate.1 Prostate cancer is often driven by male sex hormones called androgens, including testosterone. 3 In patients with mCRPC, prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.3 Approximately 10-20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these men will have metastases at the time of CRPC diagnosis. 4 Of men with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years. 4 Despite advances in treatment for men with mCRPC, five-year survival is low and extending survival remains a key treatment goal.4

BRCA mutations

BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role in maintaining the genetic stability of cells. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer and confer sensitivity to PARP inhibitors including Lynparza.5-8

PROfound

PROfound is a prospective, multicentre, randomised, open-label, Phase III trial testing the efficacy and safety of Lynparza versus enzalutamide or abiraterone in patients with mCRPC who have progressed on prior treatment with NHA treatments (abiraterone or enzalutamide) and have a qualifying tumour mutation in BRCA1/2, ATM or one of 12 other genes involved in the HRR pathway.

The trial was designed to analyse patients with HRR gene mutations in two cohorts: the primary endpoint was rPFS in those with mutations in BRCA1/2 or ATM genes and then, if Lynparza showed clinical benefit, a formal analysis was performed of the overall trial population of patients with HRR gene mutations (BRCA1/2, ATM, CDK12 and 11 other HRR gene mutations). AstraZeneca and MSD announced in August 2019 that the trial met its primary endpoint of rPFS.

Lynparza

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in HRR, such as mutations in BRCA1 and/or BRCA2. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR pathway.

Lynparza is currently approved in a number of countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer. It is approved in the US, the EU, Japan, China, and several other countries as 1st-line maintenance treatment of BRCAm advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in the US as a 1st-line maintenance treatment with bevacizumab for patients with HRD-positive advanced ovarian cancer (BRCAm and/or genomic instability). Lynparza is approved in the US, Japan, and a number of other countries for germline BRCAm, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer. It is also approved in the US, the EU and several other countries for the treatment of germline BRCAm metastatic pancreatic cancer. Lynparza is approved in the US for HRR gene-mutated mCRPC (BRCAm and other HRR gene mutations). Regulatory reviews are underway in several countries for ovarian, breast, pancreatic and prostate cancers.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 30,000 patients worldwide. Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

The AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and Koselugo (selumetinib), a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On November 5, 2020 ERYTECH Pharma (Nasdaq & Euronext: ERYP), a clinical-stage biopharmaceutical company developing innovative therapies by encapsulating therapeutic drug substances inside red blood cells, reported that an abstract detailing results from the NOPHO sponsored Phase 2 trial of eryaspase in ALL patients, has been selected for oral presentation at the upcoming 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting being held virtually December 5-8 (Press release, ERYtech Pharma, NOV 5, 2020, View Source [SID1234570037]). A second abstract detailing population pharmacokinetics of eryaspase in ALL or pancreatic adenocarcinoma patients has been accepted for a poster presentation at the meeting.

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On November 5, 2020 Race Oncology Limited (ASX: RAC) reported that the clinical data from the investigator initiated Phase II clinical trial of Bisantrene in relapsed and refractory Acute Myeloid Leukaemia (R/R AML), conducted at Israel’s Sheba Medical Centre has been accepted for presentation at the American Society for Haematology 2020 Conference (ASH 2020) (Press release, Race Oncology, NOV 5, 2020, View Source [SID1234570036]).

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This open label, single agent trial, led by Professor Arnon Nagler, studied patients (n=10) with relapsed or refractory Acute Myeloid Leukaemia (R/R AML) who on average had failed three prior lines of treatment. Bisantrene was found to be well tolerated, and after only a single course of treatment, had an overall clinical response rate of 40% (ASX Announcement: June 16 2020).

The ASH (Free ASH Whitepaper) Annual Meeting is the premier international clinical conference for malignant and non-malignant haematology and attracts over 30,000 attendees across four days. The annual meeting presentations are chosen by peer-review and cover the latest developments in scientific and clinical research in the field of haematology.

The presentation, entitled "A Phase II Study of Bisantrene in Patients with Relapsed/ Refractory Acute Myeloid Leukemia" will be presented on 5 December 2020. The abstract for this presentation is available via: