PARP1 inhibitors(Poly (ADP-Ribose) polymerase 1 inhibitors), PARP2 inhibitors(Poly (ADP-Ribose) Polymerase 2 inhibitors), PARP3 inhibitors(Poly (ADP-Ribose) Polymerase 3 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [11]

Active Indication

Castration-Resistant Prostatic CancerPancreatic CancerPancreatic Carcinoma+ [122]

Inactive Indication

Advanced Endometrial CarcinomaAdvanced Prostate CarcinomaBRCA-Associated Ovarian Carcinoma+ [26]

Originator Organization

AstraZeneca PLC

Active Organization

Novartis Pharmaceuticals Corp.

The Gynecologic Oncology Group

AstraZeneca Investment (China) Co. Ltd.

+ [38]

Inactive Organization

The Institute of Cancer Research: Royal Cancer HospitalRoyal Marsden NHS Foundation Trust

The Vanderbilt-Ingram Cancer Center

+ [11]

Drug Highest PhaseApproved

First Approval Date

EU (16 Dec 2014),

Adenocarcinoma, metastaticBRCA Mutation Castration-Resistant Prostate CancerBRCA-mutated Fallopian Tube Carcinoma+ [14]

RegulationPriority Review (US), Breakthrough Therapy (US), Fast Track (US), Accelerated Approval (US), Orphan Drug (US), Priority Review (CN), Special Review Project (CN), Orphan Drug (JP), Priority Review (AU), Accelerated Approval (CA)

Structure

Molecular FormulaC24H23FN4O3

InChIKeyFDLYAMZZIXQODN-UHFFFAOYSA-N

CAS Registry763113-22-0

521

Clinical Trials associated with Olaparib

NCT06419179 / Not yet recruitingPhase 2IIT

A Multicenter Phase II Trial of Maintenance Durvalumab (MEDI4736) and Olaparib (AZD2281) After Standard 1st Line Treatment (Carboplatin/Cisplatin, Etoposide, Durvalumab) in Homologous Recombination Deficiency (HRD) Positive Extensive Disease (ED) Small-cell Lung Cancer (SCLC)

Maintenance durvalumab (MEDI4736) and olaparib (AZD2281) after standard 1st line treatment (carboplatin/ cisplatin, etoposide, durvalumab) in HRD positive extensive disease (ED) small-cell lung cancer (SCLC)

Start Date01 Sep 2024

Sponsor / Collaborator

University of Cologne Executive School GmbH

[+1]

NCT06441747 / Not yet recruitingPhase 2IIT

Phase II Study of the Combination of Durvalumab (MEDI4736) (PDL1 Inhibitor) and Olaparib (PARP Inhibitor) in Advanced Cholangiocarcinoma After Initial Chemotherapy and Durvalumab (BIL-PPP)

The aim of this study is to investigate whether the combination of durvalumab and olaparib in the maintenance setting after initial chemotherapy and durvalumab will benefit patients with locally advanced or metastatic cholangiocarcinoma.

Start Date01 Aug 2024

Sponsor / Collaborator

AstraZeneca PLC

NCT05128734 / Not yet recruitingPhase 2IIT

A Randomized Phase II Study of Temozolomide Monotherapy or in Combination With Olaparib in Patients With METHYLATED 06-Methylguanine-DNA Methyltransferase (MGMT) Pre-Treated Triple Negative Breast Cancer (TNBC)

This is a randomized phase II study to evaluate the disease control rate (DCR) of patients with metastatic or locally advanced METHYLATED 06-methylguanine-DNA methyltransferase (MGMT) with triple-negative breast cancer (TNBC) treated with Temozolomide ± Olaparib. Patients will be randomized 1:1 to Treatment Arm 1 (temozolomide treatment) or Arm 2 (temozolomide plus olaparib treatment).

Start Date01 Jul 2024

Sponsor / Collaborator

AHS Cancer Control Alberta

100 Clinical Results associated with Olaparib

100 Translational Medicine associated with Olaparib

100 Patents (Medical) associated with Olaparib

2,678

Literatures (Medical) associated with Olaparib

01 Jan 2024·Journal of cancer research and clinical oncology

Human papillomavirus E7 protein induces homologous recombination defects and PARPi sensitivity

Article

Author: Zhao, Mingcai ; Wang, Ao ; He, Siqi ; Chen, Hui ; Chen, Jie ; Song, Liang ; Wang, Jing ; Tang, Zizhi ; Wang, Danqing ; Liu, Cong ; Wang, Xiaojun

Abstract:

Purpose:

Cervical cancer is a common gynecological malignancy, pathologically associated with persistent infection of high-risk types of human papillomavirus (HPV). Previous studies revealed that HPV-positive cervical cancer displays genomic instability; however, the underlying mechanism is not fully understood.

Methods:

To investigate if DNA damage responses are aggravated in precancerous lesions of HPV-positive cervical epithelium, cervical tissues were biopsied and cryosectioned, and subjected to immunofluorescent staining. Cloned HA-tagged E6 and E7 genes of HPV16 subtype were transfected into HEK293T or C33A cells, and indirect immunofluorescent staining was applied to reveal the competency of double strand break (DSB) repair. To test the synthetic lethality of E7-indued HRD and PARP inhibitor (PARPi), we expressed E7 in C33A cells in the presence or absence of olaparib, and evaluated cell viability by colony formation.

Results:

In precancerous lesions, endogenous DNA lesions were elevated along with the severity of CIN grade. Expressing high-risk viral factor (E7) in HPV-negative cervical cells did not impair checkpoint activation upon genotoxic insults, but affected the potential of DSB repair, leading to homologous recombination deficiency (HRD). Based on this HPV-induced genomic instability, the viability of E7-expressing cells was reduced upon exposure to PARPi in comparison with control cells.

Conclusion:

In aggregate, our findings demonstrate that HPV-E7 is a potential driver for genome instability and provides a new angle to understand its role in cancer development. The viral HRD could be employed to target HPV-positive cervical cancer via synthetic lethality.

01 Mar 2024·International journal of cancer

Differences in time to patient access to innovative cancer medicines in six European countries

Article

Author: Vancoppenolle, Julie M ; Retèl, Valesca P ; Koole, Simone N ; van Harten, Wim H ; Franzen, Nora

Abstract:

Patients across Europe face inequity regarding access to anticancer medicines. While access is typically evaluated through reimbursement status or sales data, patients can receive first access through early access programs (EAPs) or off‐label use. This study aims to assess the time to patient access at the hospital level, considering different indications and countries. (Pre‐)registered access to six innovative medicines (Olaparib, Niraparib, Ipilimumab, Osimeritinib, Nivolumab and Ibritunib) was measured using a cross‐sectional survey. First patient access to medicines and indications were collected using the hospital databases. Nineteen hospitals from Hungary, Italy, the Netherlands, Belgium, Switzerland and France participated. Analysis showed that some hospitals achieved patient access before national reimbursement, primarily through EAPs. The average time from EMA‐approval to patient access for these medicines was 2.1 years (Range: −0.9‐7.1 years). Hospitals in Italy and France had faster access compared to Hungary and Belgium. Variation was also found within countries, with specialized hospitals (x̄: −0.9 years; SD: 2.0) more likely to provide patient access prior to national reimbursement than general hospitals (x̄: 0.4 years; SD: 2.9). Contextual differences were observed, with EAPs or off‐label use being more prevalent in Switzerland than Hungary. Recent EMA‐approved indications and drug combinations reached patients at a later stage. Substantial variation in patient access time was observed between and within countries. Improving pricing and reimbursement timelines, fostering collaboration between national health authorities and market authorization holders, and implementing nationally harmonized, data‐generating EAPs can enhance timely and equitable patient access to innovative cancer treatments in Europe.

22 Feb 2024·Journal of medicinal chemistryQ1 · MEDICINE

Discovery of the Potent and Selective ATR Inhibitor Camonsertib (RP-3500)

Q1 · MEDICINE

Article

Author: Truchon, Jean-François ; Pellerin, Charles ; Black, W Cameron ; Beaulieu, Patrick ; Roulston, Anne ; Zimmermann, Michal ; Mulani, Amina ; Ferraro, Gino B ; Dorich, Stéphane ; Diallo, Mohamed ; Mamane, Yael ; Abdoli, Abbas ; Skeldon, Alexander ; Chefson, Amandine ; Auger, Anick ; Crane, Sheldon ; Fournier, Sara ; Caron, Cathy ; Gao, Qi ; Stocco, Rino ; Lanoix, Stéphanie ; An, Xiuli ; Picard, Audrey ; St-Onge, Miguel ; Ginzburg, Yelena ; Truong, Vouy Linh ; Skorey, Kathryn ; Levy, Maayan ; Lacbay, Cyrus M ; Hamel, Martine ; Bernatchez, Michel ; Jones, Paul ; Papp, Robert ; Leclaire, Marie-Eve ; Han, Yongshuai ; Zinda, Michael ; Fader, Lee D

ATR is a key kinase in the DNA-damage response (DDR) that is synthetic lethal with several other DDR proteins, making it an attractive target for the treatment of genetically selected solid tumors. Herein we describe the discovery of a novel ATR inhibitor guided by a pharmacophore model to position a key hydrogen bond. Optimization was driven by potency and selectivity over the related kinase mTOR, resulting in the identification of camonsertib (RP-3500) with high potency and excellent ADME properties. Preclinical evaluation focused on the impact of camonsertib on myelosuppression, and an exploration of intermittent dosing schedules to allow recovery of the erythroid compartment and mitigate anemia. Camonsertib is currently undergoing clinical evaluation both as a single agent and in combination with talazoparib, olaparib, niraparib, lunresertib, or gemcitabine (NCT04497116, NCT04972110, NCT04855656). A preliminary recommended phase 2 dose for monotherapy was identified as 160 mg QD given 3 days/week.

384

News (Medical) associated with Olaparib

20 Jun 2024

·pipelinereview.com

Truqap plus Faslodex approved in the EU for patients with advanced ER-positive breast cancer

First and only AKT inhibitor approved in the EU for breast cancer patients with specific biomarker alterations (PIK3CA, AKT1 or PTEN) Approval based on CAPItello-291 results which showed this combination reduced the risk of disease progression or death by 50% vs. Faslodex alone in a biomarker-altered population LONDON, UK I June 20, 2024 I AstraZeneca’s Truqap (capivasertib) in combination with Faslodex (fulvestrant) has been approved in the European Union (EU) for the treatment of adult patients with estrogen receptor (ER)-positive, HER2‑negative locally advanced or metastatic breast cancer with one or more PIK3CA, AKT1, or PTEN-alterations following recurrence or progression on or after an endocrine-based regimen. The approval by the European Commission follows the positive opinion of the Committee for Medicinal Products for Human Use and is based on results from the CAPItello-291 Phase III trial published in The New England Journal of Medicine . 1 In the trial, Truqap in combination with Faslodex reduced the risk of disease progression or death by 50% versus Faslodex in combination with placebo in patients with tumours harbouring PI3K, AKT or PTEN alterations (based on hazard ratio of 0.50, 95% confidence interval 0.38-0.65; p=<0.001; median progression-free survival (PFS) 7.3 versus 3.1 months). 1 In Europe, breast cancer remains the leading cause of cancer death, with more than 140,000 deaths in 2022 and more than 550,000 patients diagnosed in the same year. 2 Hormone receptor (HR)-positive breast cancer (expressing estrogen or progesterone receptors, or both), is the most common subtype of breast cancer with 70% of tumours considered HR-positive and HER2-negative. 3 More than 97% of HR-positive breast cancer tumours are ER-positive. 4,5 Collectively, mutations in PIK3CA, AKT1 and alterations in PTENoccur frequently, affecting approximately 50% of patients with advanced HR-positive breast cancer. 6-8 Mafalda Oliveira, MD, PhD, Vall d’Hebron University Hospital, and Senior Clinical Investigator of the Vall d’Hebron Institute of Oncology’s Breast Cancer Group in Barcelona, Spain, said: “Patients with advanced ER-positive breast cancer typically experience tumour progression or resistance with widely used endocrine-based treatment regimens, and there is an urgent need to provide them more time with their disease under control. Today’s approval is welcome news for approximately half of ER-positive breast cancer patients in Europe who have tumours with these biomarkers, and it is important for clinicians to test and identify eligible patients who may be able to benefit from this combination.” Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: “ Truqap is now the first and only AKT inhibitor approved in the European Union for patients with ER-positive breast cancer who have tumours harbouring these specific biomarkers. Breast cancer continues to be the leading cause of cancer-related death in Europe, and today’s news represents a significant step forward in providing an important new treatment option for patients in need of new, innovative therapies.” In the CAPItello-291 trial, the safety profile of Truqap plus Faslodex was similar to that observed in previous trials evaluating this combination. 1 Regulatory applications are currently under review in China and several other countries. Similar indications for Truqap in combination with Faslodex are already approved in the US , Japan and several other countries based on the CAPItello-291 trial. Financial considerations Following this approval in the EU, Astex Therapeutics is eligible to receive a milestone payment from AstraZeneca on first commercial sale of the drug in the EU as well as royalties on future sales in line with the agreement between the two companies. Notes HR-positive breast cancer The growth of HR-positive breast cancer cells is often driven by estrogen receptors, and endocrine therapies that target ER-driven disease are widely used as 1st-line treatment in the advanced setting, and often paired with CDK4/6 inhibitors. 9-11 However, resistance to CDK4/6 inhibitors and current endocrine therapies develops in many patients with advanced disease. 10 Once this occurs, treatment options are limited– with chemotherapy being the current standard of care – and survival rates are low with approximately 35% of patients anticipated to live beyond five years after diagnosis. 3,10,12 The optimisation of endocrine therapy and overcoming resistance to enable patients to continue benefiting from these treatments, as well as identifying new therapies for those who are less likely to benefit, are active areas of focus for breast cancer research. CAPItello-291 CAPItello-291 is a Phase III, double-blind, randomised trial evaluating the efficacy of Truqap in combination with Faslodex versus placebo plus Faslodex for the treatment of locally advanced (inoperable) or metastatic HR-positive (ER-positive and ER-positive, progesterone receptor-positive), HER2-low or negative (immunohistochemistry (IHC) 0 or 1+, or IHC 2+/in-situ hybridisation (ISH)-negative) breast cancer. The global trial enrolled 708 adult patients with histologically confirmed HR-positive, HER2-low or negative breast cancer whose disease has recurred or progressed during or after aromatase inhibitor therapy, with or without a CDK4/6 inhibitor, and up to one line of chemotherapy for advanced disease. The trial has dual primary endpoints of PFS in the overall patient population and in a population of patients whose tumours have qualifying alterations in the PI3K/AKT pathway (PIK3CA, AKT1 or PTEN genes). In the trial, approximately 40% of tumours had these alterations and approximately 70% of patients received a prior CDK4/6 inhibitor. Truqap Truqap is a first-in-class, potent, adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3). Truqap 400mg is administered twice daily according to an intermittent dosing schedule of four days on and three days off. This was chosen in early phase trials based on tolerability and the degree of target inhibition. Truqap is approved in the US, EU, Japan and several other countries for the treatment of adult patients with HR-positive (or ER-positive), HER2-negative locally advanced or metastatic breast cancer with one or more biomarker alterations (PIK3CA, AKT1 or PTEN) following recurrence or progression on or after an endocrine-based regimen based on the results from the CAPItello-291 trial. Truqap is also approved in Australia for the treatment of adult patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer following recurrence or progression on or after an endocrine based regimen based on these trial results. Truqap is currently being evaluated in Phase III trials for the treatment of breast cancer (CAPItello-292) and prostate cancer (CAPItello-280 and CAPItello-281) in combination with established treatments. Truqap was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited). Faslodex Faslodex is an endocrine therapy indicated for the treatment of ER-positive, locally advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy, or with disease relapse on or after adjuvant anti-estrogen therapy, or disease progression on anti-estrogen therapy. In the US, EU and Japan , Faslodex is also approved in combination with CDK4/6 inhibitors for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer, whose cancer has progressed after endocrine medicine . Faslodex represents a hormonal treatment approach that helps to slow tumour growth by blocking and degrading the estrogen receptor – a key driver of disease progression. Faslodex is approved as monotherapy or in combination with medicines from various drug classes including CDK4/6, PI3K and AKT inhibitors for the treatment of patients with HR-positive advanced breast cancer and is being evaluated in combination with medicines from other drug classes. AstraZeneca in breast cancer Driven by a growing understanding of breast cancer biology, AstraZeneca is starting to challenge, and redefine, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need – with the bold ambition to one day eliminate breast cancer as a cause of death. AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumour environment. With Enhertu (trastuzumab deruxtecan), a HER2-directed antibody drug conjugate (ADC), AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in previously treated HER2-positive and HER2-low metastatic breast cancer and are exploring its potential in earlier lines of treatment and in new breast cancer settings.. In HR-positive breast cancer, AstraZeneca continues to improve outcomes with foundational medicines Faslodex and Zoladex (goserelin) and aims to reshape the HR-positive space with first-in-class AKT inhibitor, Truqap , and next-generation SERD and potential new medicine camizestrant. AstraZeneca is also collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan, in this setting. PARP inhibitor Lynparza (olaparib) is a targeted treatment option that has been studied in early and metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with MSD (Merck & Co., Inc. in the US and Canada) continue to research Lynparza in these settings and to explore its potential in earlier disease. To bring much-needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is evaluating the potential of datopotamab deruxtecan alone and in combination with immunotherapy Imfinzi (durvalumab), and Imfinzi in combination with other oncology medicines, including Lynparza and Enhertu . AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. AstraZeneca AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca’s innovative medicines are sold in more than 125 countries and used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on social media @AstraZeneca References SOURCE: AstraZeneca

Phase 3Drug ApprovalClinical ResultImmunotherapy

18 Jun 2024

·pipelinereview.com

Update on the CAPItello-290 Phase III trial for Truqap plus chemotherapy in advanced or metastatic triple-negative breast cancer

LONDON, UK I June 18, 2024 I The CAPItello-290 Phase III trial for Truqap (capivasertib) in combination with paclitaxel in patients with locally advanced (inoperable) or metastatic triple-negative breast cancer (TNBC) did not meet the dual primary endpoints of improvement in overall survival (OS) versus paclitaxel in combination with placebo in either the overall trial population or in a subgroup of patients with tumours harbouring specific biomarker alterations (PIK3CA, AKT1 or PTEN). Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide. 1 While some breast cancers may test positive for estrogen receptors, progesterone receptors or overexpression of human epidermal growth factor receptor 2 (HER2), TNBC is defined as negative for all three. 2 In the 1st-line setting, approximately 59,000 patients with TNBC are treated with a medicine. 3 Collectively, mutations in PIK3CA, AKT1 and alterations in PTEN affect approximately 35% of patients with TNBC. 4 Peter Schmid, MD, Barts Cancer Institute, London, UK, and principal investigator for the trial said: “Despite modest advances, triple-negative breast cancer remains one of the most challenging forms of disease to treat due to the lack of known actionable biomarker targets, and chemotherapy-based regimens continue to be the mainstay of treatment. While the CAPItello-290 trial results have not shown what we hoped, they provide important information to further understand this aggressive form of breast cancer where patients are in urgent need of new treatments.” Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “We are committed to advancing science for patients in some of the most challenging cancers, including this heterogeneous subtype of breast cancer. While we are disappointed in the CAPItello-290 outcome, these results will further our understanding of the role of the PI3K/AKT pathway in breast cancer as we continue our clinical research across the Truqap clinical development programme and across our pipeline.” The safety profile of Truqap in combination with paclitaxel in CAPItello-290 was broadly consistent with the known safety profile of each medicine with no new safety concerns identified. Data will be shared in due course. Truqap is currently being evaluated in Phase III trials for the treatment of breast cancer (CAPItello-292) and prostate cancer (CAPItello-280 and CAPItello-281) in combination with established treatments. Notes Triple-negative breast cancer 1st-line treatment for advanced or metastatic TNBC usually consists of chemotherapy alone or in combination with an immunotherapy – options generally associated with response rates between 30 to 50%. 2,5,6 Among patients with tumours that do respond to initial treatment, disease progression is common and rapid, often occurring within two years. 2,6-8 The average overall survival of patients living with advanced or metastatic TNBC is 12 to 18 months, with only about 14% of patients living five years following diagnosis. 9,10 CAPItello-290 CAPItello-290 is a Phase III, double-blind, randomised trial evaluating the efficacy and safety of Truqap in combination with paclitaxel versus placebo in combination with paclitaxel in the 1st-line treatment of patients with locally advanced (inoperable) or metastatic TNBC. The global trial enrolled 923 adult patients with histologically confirmed locally advanced or metastatic TNBC. The trial has dual primary endpoints of OS in the overall patient population and in a population of patients whose tumours have qualifying alterations in the PI3K/AKT pathway (PIK3CA, AKT1 or PTEN genes). Truqap Truqap is a first-in-class, potent, adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3). Truqap 400mg is administered twice daily according to an intermittent dosing schedule of four days on and three days off. This was chosen in early phase trials based on tolerability and the degree of target inhibition. Truqap is approved in the US, Japan and several other countries for the treatment of adult patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer with one or more biomarker alterations (PIK3CA, AKT1 or PTEN) following recurrence or progression on or after an endocrine-based regimen based on the results from the CAPItello-291 trial. Truqap is also approved in Australia for the treatment of adult patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer following recurrence or progression on or after an endocrine based regimen based on these trial results. Truqap is currently being evaluated in Phase III trials for the treatment of breast cancer (CAPItello-292) and prostate cancer (CAPItello-280 and CAPItello-281) in combination with established treatments. Truqap was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited). AstraZeneca in breast cancer Driven by a growing understanding of breast cancer biology, AstraZeneca is starting to challenge, and redefine, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need – with the bold ambition to one day eliminate breast cancer as a cause of death. AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumour environment. With Enhertu (trastuzumab deruxtecan), a HER2-directed antibody drug conjugate (ADC), AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in previously treated HER2-positive and HER2-low metastatic breast cancer and are exploring its potential in earlier lines of treatment and in new breast cancer settings. In HR-positive breast cancer, AstraZeneca continues to improve outcomes with foundational medicines Faslodex and Zoladex (goserelin) and aims to reshape the HR-positive space with first-in-class AKT inhibitor, Truqap , and next-generation SERD and potential new medicine camizestrant. AstraZeneca is also collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan, in this setting. PARP inhibitor Lynparza (olaparib) is a targeted treatment option that has been studied in early and metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with MSD (Merck & Co., Inc. in the US and Canada) continue to research Lynparza in these settings and to explore its potential in earlier disease. To bring much-needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is evaluating the potential of datopotamab deruxtecan alone and in combination with immunotherapy Imfinzi (durvalumab), and Imfinzi in combination with other oncology medicines, including Lynparza and Enhertu . AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. AstraZeneca AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on social media @ AstraZeneca . References SOURCE: AstraZeneca

Phase 3Clinical ResultDrug ApprovalImmunotherapyADC

17 Jun 2024

·www.fiercepharma.com

AstraZeneca lands narrow Imfinzi nod in endometrial cancer. Where’s Lynparza?

With the narrowed label, AstraZeneca said it's still working with the FDA to determine next steps to potentially bring Imfinzi with or without Lynparza to a broader endometrial cancer population. AstraZeneca’s Imfinzi has followed GSK’s Jemperli into endometrial cancer. And like its compatriot competitor, the FDA approval is limited to a subgroup of patients. The new approval is for Imfinzi, used in combination with chemotherapy followed by Imfinzi alone, to treat certain patients with primary advanced or recurrent endometrial cancer. In a key limitation, the cancer must be mismatch repair deficient (dMMR), a type of genetic abnormality, AZ said Monday. The dMMR-only nod matches the first immunotherapy approval that the FDA handed to GSK’s Jemperli as an add-on to chemotherapy in July 2023. Although AZ’s oncology business chief Dave Fredrickson in a Monday statement touted Imfinzi as “an important new option” for the first-line treatment of dMMR endometrial cancer, two questions remain for the PD-1/L1 inhibitor class in the broader endometrial cancer field. First of all, the FDA seemed to have turned away AZ’s proposed combination that further adds the Merck & Co.-partnered PARP inhibitor Lynparza on top of Imfinzi during the maintenance phase. In AZ’s most recent investor updates, the company has been listing the Imfinzi-Lynparza regimen as awaiting an FDA decision in first-line endometrial cancer. In response to a Fierce Pharma inquiry, an AZ spokesperson didn’t directly answer whether the company had filed the Imfinzi-Lynparza combo with the FDA and got a rejection. “We are continuing to assess overall survival (OS) for both [Imfinzi] monotherapy and [Imfinzi] plus [Lynparza] as maintenance therapy in the overall trial population and are working with the U.S. FDA to determine next steps to provide additional treatment options to even more patients,” the spokesperson said. The spokesperson was referring to the phase 3 DUO-E trial. In a prespecified subgroup analysis, Imfinzi and chemo cut the risk of tumor progression or death by 58% compared with chemo alone in dMMR patients. The Imfinzi-chemo regimen also slashed the risk of death by 66% in this subgroup at the interim analysis. Those data formed the basis of the current approval. Imfinzi and chemo also offered a 23% improvement in progression-free survival (PFS) in the larger mismatch repair proficient group (pMMR), and a marginal 9% reduction in the risk of death. It’s not clear whether AZ had sought a broader indication that included the pMMR population for Imfinzi and chemo. The Imfinzi-Lynparza-chemo regimen appeared to have offered limited additional benefit in the dMMR population with very similar PFS and OS improvements compared with the Imfinzi-chemo pairing. AZ has also acknowledged that the incremental benefit for Lynparza was more pronounced in the pMMR group, in which it has shown PFS and OS benefits at 43% and 31%, respectively, compared with chemo alone at the interim analysis. The FDA has become very cautious with PAPR inhibitors after some long-term data in ovarian cancer pointed to potential harm to certain later-line patients without BRCA mutations. AZ and Lynparza felt that extra scrutiny last year when the FDA restricted an approval in metastatic prostate cancer to only BRCA-mutated tumors. Now, it appears that AZ will need longer follow-ups to convince the FDA of Lynparza’s use in endometrial cancer as well. The second question concerns AZ’s PD-1 competitors: GSK’s Jemperli and Merck’s Keytruda. Although Jemperli and chemo’s initial nod in first-line endometrial cancer was only for dMMR patients, GSK has followed the phase 3 RUBY trial longer and recently got FDA priority review for its new application in the overall population. The target decision date is August 23. However, GSK has yet to make a move for its combination that includes the PARP inhibitor Zejula. Part 2 of GSK’s RUBY trial showed a similar pattern as AZ’s DUO-E, as the addition of Zejula to Jemperli and chemo only appeared to have meaningful benefits in pMMR tumors. As to Merck, the New Jersey pharma has its application for Keytruda and chemo in first-line endometrial cancer under FDA priority review, with a target action date of June 21. Data from the phase 3 NRG-GY018 trial released last year showed the Keytruda-chemo combo improved PFS by 46% in pMMR patients and by 70% in dMMR. However, investigators of the study noted back then that the follow-up time for pMMR patients was too short.

Phase 3Clinical ResultDrug ApprovalPriority ReviewImmunotherapy

100 Deals associated with Olaparib

External Link

KEGG	Wiki	ATC	Drug Bank
D09730	Olaparib	L01XX46	DB09074

R&D Status

Approved

10 top approved records.

to view more data

Indication	Country/Location	Organization	Date
Castration-Resistant Prostatic Cancer	CN	AstraZeneca PLC	16 Jun 2021
Pancreatic Cancer	JP	AstraZeneca KK	25 Dec 2020
Pancreatic Carcinoma	JP	MSD KK	25 Dec 2020
HRD-positive Ovarian Cancer	US	AstraZeneca Pharmaceuticals LP	19 May 2020
HRR Gene-mutated Castration-Resistant Prostate Cancer	US	AstraZeneca Pharmaceuticals LP	19 May 2020
Germline BRCA-mutated Pancreatic Adenocarcinoma	US	AstraZeneca Pharmaceuticals LP	27 Dec 2019
Recurrent HER2-Negative Breast Carcinoma	JP	MSD KK	02 Jul 2018
Recurrent HER2-Negative Breast Carcinoma	JP	AstraZeneca KK	02 Jul 2018
BRCA-mutated Ovarian Cancer	US	AstraZeneca Pharmaceuticals LP	19 Dec 2014
Adenocarcinoma, metastatic	EU	AstraZeneca AB	16 Dec 2014
Adenocarcinoma, metastatic	IS	AstraZeneca AB	16 Dec 2014
Adenocarcinoma, metastatic	LI	AstraZeneca AB	16 Dec 2014
Adenocarcinoma, metastatic	NO	AstraZeneca AB	16 Dec 2014
BRCA Mutation Castration-Resistant Prostate Cancer	EU	AstraZeneca AB	16 Dec 2014
BRCA Mutation Castration-Resistant Prostate Cancer	IS	AstraZeneca AB	16 Dec 2014
BRCA Mutation Castration-Resistant Prostate Cancer	LI	AstraZeneca AB	16 Dec 2014
BRCA Mutation Castration-Resistant Prostate Cancer	NO	AstraZeneca AB	16 Dec 2014
BRCA-mutated Fallopian Tube Carcinoma	EU	AstraZeneca AB	16 Dec 2014
BRCA-mutated Fallopian Tube Carcinoma	IS	AstraZeneca AB	16 Dec 2014
BRCA-mutated Fallopian Tube Carcinoma	LI	AstraZeneca AB	16 Dec 2014

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Ovarian Serous Adenocarcinoma	Phase 3	US	Novartis Pharmaceuticals Corp.	02 Jul 2021
Ovarian Serous Adenocarcinoma	Phase 3	CN	Novartis Pharmaceuticals Corp.	02 Jul 2021
Ovarian Serous Adenocarcinoma	Phase 3	AR	Novartis Pharmaceuticals Corp.	02 Jul 2021
Ovarian Serous Adenocarcinoma	Phase 3	AU	Novartis Pharmaceuticals Corp.	02 Jul 2021
Ovarian Serous Adenocarcinoma	Phase 3	AT	Novartis Pharmaceuticals Corp.	02 Jul 2021
Ovarian Serous Adenocarcinoma	Phase 3	BE	Novartis Pharmaceuticals Corp.	02 Jul 2021
Ovarian Serous Adenocarcinoma	Phase 3	BR	Novartis Pharmaceuticals Corp.	02 Jul 2021
Ovarian Serous Adenocarcinoma	Phase 3	CA	Novartis Pharmaceuticals Corp.	02 Jul 2021
Ovarian Serous Adenocarcinoma	Phase 3	CZ	Novartis Pharmaceuticals Corp.	02 Jul 2021
Ovarian Serous Adenocarcinoma	Phase 3	DK	Novartis Pharmaceuticals Corp.	02 Jul 2021

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03498521 (CUPISCO, CTgov)	Phase 2	Neoplasms	528	platinum (Molecularly-Guided Therapy MGT) Category 1)	dioevlniwy(ksrewwlsab) = uyqcimzafm xomwbljtcc (dtrvwecqzf, ecpjundfsa - qkqnmnqquf) View more	-	14 Jun 2024
				platinum (Chemotherapy Category 1)	dioevlniwy(ksrewwlsab) = lbqtyamwbw xomwbljtcc (dtrvwecqzf, fbeqrcfykr - hqprrutapr) View more
NCT04417192 (OLAPem, ASCO2024) Manual	Phase 2	Ovarian Epithelial Carcinoma Neoadjuvant HRD Positive \| BRCA1 Mutation \| BRCA2 Mutation	20	olaparib+pembrolizumab	pchwwjkynv(qfnptrzjqi) = rpxfwgkdzf lcpqowelhp (kpuwvacezc, 45.7-88.1) View more	Positive	24 May 2024
NCT03534453 (L-MOCA, ASCO2024)	Phase 3	Recurrent ovarian cancer Maintenance BRCAmutation \| homologous recombination deficiency (HRD)	224	Olaparib 300 mg	reqjxdurcs(mmdhgkgess) = Adverse events of any grade occurred in 222 (99.1%) patients. The incidence of myelodysplastic syndrome and acute myeloid leukemia remained low (3 [1.3%]). No new safety signals were identified. ysqpcucroh (esoqsgfzgo )	Positive	24 May 2024
NCT04939662 (SUKSES-B2, ASCO2024)	Phase 2	Small cell lung cancer recurrent SLFN11 \| POU2F3 \| DDR pathway alterations ... View more	25	Olaparib 300mg	jodwbxrzhs(dzqzkiawhu) = slvzsdyazs muqchxeyic (hvjlnvqikd ) View more	Positive	24 May 2024
NCT03161132 (ROLANDO-GEICO 1601, ASCO2024)	Phase 2	Platinum-Resistant Ovarian Carcinoma RAGE	31	olaparib	cddudvfoas(fljryawcbj) = jkyebxefvg yqstczvbok (gwwtgickbv ) View more	Positive	24 May 2024
				olaparib	cddudvfoas(fljryawcbj) = xpxcikeols yqstczvbok (gwwtgickbv ) View more
NCT02489006 (NEO, ASCO2024)	Phase 2	Recurrent ovarian cancer Neoadjuvant wtBRCA1/2 \| germlineBRCA1/2mutation	44	Olaparib 300mg po bid	qggrylcawj(csvmlzmtja) = ybtcptvakr dafnqdhstx (skmjfrecit, 69.3% - 100%) View more	Positive	24 May 2024
				Platinum chemotherapy followed by maintenance olaparib	qggrylcawj(csvmlzmtja) = ydeqnfmqnp dafnqdhstx (skmjfrecit, 56.6% - 99.7%) View more
NCT06121401 (IOLANTHE, ASCO2024)	Phase 4	HRD-positive Ovarian Cancer Maintenance HRD+	190	Olaparib + Bevacizumab	ilcvtkywdi(pkyyndvzos) = ubklhbinpd rrwxtvqijf (rooglnielx )	Positive	24 May 2024
NCT02503436 (C-PATROL, ASCO2024)	Not Applicable	BRCA-mutated Ovarian Cancer Maintenance BRCA-mutated	277	Olaparib maintenance	bynvetbhal(mmirxnzshi) = gndrfbihng vxvwusxxor (nlziloegai, 29.2 - 49.9)	Positive	24 May 2024
NCT02032823 (TBCRC 048, ASCO2024)	Phase 2	gPALB2 \| sBRCA1 \| sBRCA2	-	Olaparib 300 mg bid	mxuowdaryc(plykrxkshg) = merujqnupe mpfvrpvduh (wljgmoydtr, 65.8% - 94.1%) View more	Positive	24 May 2024
				Placebo	mxuowdaryc(plykrxkshg) = mznuasargn mpfvrpvduh (wljgmoydtr, 37% - 69.2%) View more
NCT02755844 (ENDOLA, ASCO2024)	Phase 1/2	Recurrent Endometrial Cancer POLE \| dMMR/MSI-high \| NSMP ... View more	35	Olaparib + metronomic cyclophosphamide + metformin	bodmnfssrc(shrpemmfmc) = ruutgkqnvg trkkkehktt (ujqkxbbiyo ) View more	Positive	24 May 2024
				Placebo	bodmnfssrc(shrpemmfmc) = nxlvbkkiml trkkkehktt (ujqkxbbiyo ) View more

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