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1 november 2018: Zie ook dit artikel:

https://kanker-actueel.nl/olaparib-als-onderhoudsbehandeling-voor-brca-12-uitgezaaide-platinum-gevoelige-eierstokkanker-geeft-70-procent-minder-kans-op-overlijden-in-vergelijking-met-placebo.html

Zie ook in gerelateerde artikelen

4 april 2018: zie ook dit artikel:

https://kanker-actueel.nl/parpremmer-rucaparib-verdubbelt-ziektevrije-overleving-5-vs-11-en-13-maanden-bij-chemo-gevoelige-eierstokkanker-ook-bij-patienten-zonder-brca-mutatie-is-rucaparib-effectief.html

6 november 2016: Lees ook dit artikel:

https://kanker-actueel.nl/NL/olaparib-een-parp-remmer-verlengt-ziektevrije-en-overall-overleving-in-vergelijking-met-placebo-bij-eierstokkanker-met-brca-1-en-2.html

en dit artikel:

https://kanker-actueel.nl/NL/niraparib-geeft-zeer-goede-resultaten-bij-recidief-van-gevorderde-eierstokkanker-die-eerder-gevoelig-bleek-voor-op-platinum-gebaseerde-chemo-copy-1.html

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Hier een zin over de diagnostische test:

BRACAnalysis CDx - een genetische test van het bedrijf dat de olaparib produceert is ontwikkeld om de aanwezigheid aan te tonen van mutaties in de BRCA genen in het bloed van patiënten met eierstokkanker. De BRCA genen zijn betrokken met het repareren van DNA schade en bij normaal functioneren onderdrukken zij tumorgroei. Vrouwen met BRCA mutaties zijn gevoeliger voor het ontwikkelen van eierstokkanker en geschat wordt dat 10 tot 15% van alle eierstokkanker is gerelateerd aan deze erfelijke BRCA mutaties.

Originele tekst: BRACAnalysis CDx - a genetic test from the company is designed to detect the presence of mutations in the BRCA genes in blood samples from patients with ovarian cancer. The BRCA genes are involved with repairing damaged DNA and normally work to suppress tumor growth. Women with BRCA mutations are more likely to get ovarian cancer, and it is estimated that 10% to 15% of all ovarian cancer is associated with these hereditary BRCA mutations.

Lees ook onderstaande informatie over behandeling met olaparib plus cedinarib.

8 oktober 2014: lees ook deze studiepublicatie:

Een combinatie behandeling van Olaparib plus Cedinarib is zeer effectief en verdubbelt progressievrije overleving bij vergevorderde eierstokkanker van 9,2 maanden naar 17,7 maanden in vergelijking met alleen olaparib of andere vergelijkbare medicijnen. Deze resultaten kunnen nog beter worden omdat de studie nog niet is afgerond.

1 mei 2013: Bron: AACR - American Association for Cancer Research

Combinatie van sapacitabine en seliciclib geeft een hoopvol therapeutisch effect bij zwaar voorbehandelde kankerpatienten met solide tumoren met onderliggende afwijkende erfelijke BRCA gen mutaties.
Enkelen patiënten - 4 uit 16 - bereikten zelfs alsnog een gedeeeltelijke of totale remissie. In de controlegroep van ook zwaar voorbehandelde kankerpatienten met geen afwijkende BRCA mutaties bereikten enkele patiënten - 6 uit 22 - stabiele ziekte. De medicijnen repareren of verwijderen cellen op DNA niveau en is een aanpak die gericht is op de receptoren.

De resultaten van deze fase I studie met totaal 38 patiënten werd gepresenteerd door hoofdauteur Geoffrey Shapiro, MD, PhD, van Early Drug Development Center het Dana-Farber Cancer Institute in Boston, Massachusetts op het AACR congres 2013.

Studie resultaten:

In de studiegroep van 16 deelnemers met een erfelijke BRCA-mutatie die vooraf vele behandelingen hadden gehad maar steeds of een recidief kregen of waarbij de behandeling niet aansloeg, bereikten 4 van hen een gedeeltelijke remissie, waaronder 1 patiënt met alvleesklierkanker, 2 patiënten met borstkanker en 1 patiënt met eierstokkanker.

Van de patiënten die goed reageerden bleek de langste totale remissie tot nu toe 78 weken te zijn en deze duurt nog voort. Ook 2 andere BRCA mutatie dragers, met borstkanker en eierstokkanker, ervaren stabiele ziekte gedurende 21 en 64 weken, respectievelijk.

Van de overige 22 patiënten (allen met normale BRCA genen) die deelnamen aan de studie, ervaarden er 6 patiënten stabiele ziekte gedurende 12 weken of langer. Deze eerste resultaten suggereren dat een BRCA mutatie een biomarker is die ervoor zorgt dat patiënten meer kans hebben op een positieve respons van deze combinatie van medicijnen, zegt dr Shapiro van het Dana-Farber Cancer Institute in Boston.

De studieresultaten zouden ook kunnen suggereren dat de medicijnen wanneer opvolgend, dus niet gelijktijdig maar achter elkaar gegeven ook op zichzelf al effectief zouden kunnen zijn. Bv. resultaten van afgenomen huidbiopten na behandeling met sapacitabine gedurende 7 opeenvolgende dagen vertoonde een 2,3 voudige toename in kankercel DNA schade geïnduceerd door de monotherapie. Na de daaropvolgende behandeling met seliciclib gedurende 3 dagen, bleek er zich extra DNA schade te hebben voorgedaan met een 0,58 voudige toename. Tegelijkertijd blijkt er een synergetische werking uit te zijn gegaan van de 2 medicijnen als ze samen worden gegeven, aldus dr. Shapiro. "Beide medicijnen samen kunnen het best gegeven worden bij patiënten met een BRCA gemuteerde vorm van kanker," zegt dr. Sapiro.

Dr. Sapiro legt uiit hoe de medicijnen werken. Ik heb dit met google translation vertaald en naar eigen inzicht en kennis aangepast maar dit is behoorlijk medisch technische taal zodat er misschien fouten in de vertaling zitten en wie die fouten herkent mail me aub redactie@kanker-actueel.nl zodat ik het aan kan passen, voor originele artikelen zie hieronder, maar zo legt dr. Sapiro het uit:

Sapacitabine is een oraal in te nemen zogeheten analoog nucleoside medicijn dat toxisch - giftig is voor kankercellen doordat het schade veroorzaakt aan hun DNA, die, indien dit niet automatisch wordt hersteld, de tumorcellen dwingt tot apoptose, zichzelf vernietigen. Omdat het BRCA eiwit essentieel is voor herstel van DNA schade veroorzaakt door sapacitabine, kunnen patiënten met mutaties die BRCA inactiveren, extra gevoelig zijn voor dit medicijn.

Het tweede geneesmiddel, seliciclib, is een zogeheten inhibitor van cycline afhankelijke kinasen (CDK's), die enzymen hebben die een rol spelen bij DNA herstel. Deze remming van het DNA herstel vergroot door sapacitabine de verzwakkiing van de kankercel.

Het team van Dana Farber heeft een aantal moleculaire bewijzen van deze stelling. "We hebben een aantal testen gedaan die daadwerkelijk aantonen dat de CDK remming van de schade die wordt veroorzaakt door sapacitabine zal toenemen door seliciclib," vertelt Dr Shapiro aan de media.

Bijwerkingen:
De meest voorkomende bijwerkingen die tijdens de studie werden gemeld waren vermoeidheid, buikpijn, diarree, obstipatie, verminderde eetlust, misselijkheid, braken, anemie, neutropenie, koorts, hoge aspartaataminotransferase, verhoogde alkalische fosfatase, verhoogde creatinine, hyperglycemie, hypofosfatemie, hoesten, en afvallen. De meerderheid van de bijwerkingen was echter mild tot matig in intensiteit.

Dr Shapiro zegt dat de fase 1 studie heeft aangetoond dat de combinatie behandeling veilig is.

Het originele persbericht Novel Drug Combination Showed Antitumor Activity in Patients With Incurable BRCA-deficient Cancers, waaruit bovengenoemd artikel door mij is gecomponeerd staat hieronder: Bron: AACR - 2013

When given sequentially, two orally available experimental drugs — sapacitabine and seliciclib — worked together to elicit antitumor effects in patients with incurable BRCA-deficient cancers

Novel Drug Combination Showed Antitumor Activity in Patients With Incurable BRCA-deficient Cancers

Patients received sapacitabine and seliciclib as sequential treatments.
Several patients with BRCA mutations achieved disease response or experienced prolonged stable disease.
BRCA mutation carrier status may be a potential biomarker for response.

WASHINGTON, D.C. — When given sequentially, two orally available experimental drugs — sapacitabine and seliciclib — worked together to elicit antitumor effects in patients with incurable BRCA-deficient cancers, according to phase I data presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10. There are no drugs yet approved specifically for this patient population.

“Since we began to enroll predominantly patients who carried a BRCA mutation in the study, we have seen several responses among those patients, as well as instances of prolonged stable disease lasting more than a year,” said Geoffrey Shapiro, M.D., Ph.D., associate professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School in Boston, Mass.

Shapiro and colleagues initially designed the phase I study to exploit preclinical results that suggested that sapacitabine and seliciclib worked together synergistically. Sapacitabine is an oral nucleoside analogue that induces single-strand damage to DNA. If the damaged DNA is not repaired, it ultimately results in cell death. Repair of sapacitabine-induced DNA damage requires BRCA proteins, suggesting that BRCA-deficient cancers may be particularly sensitive.

Seliciclib inhibits cyclin-dependent kinases (CDKs); CDK inhibition has been shown to augment cancer cell death induced by drugs like sapacitabine by multiple mechanisms, in part by suppressing DNA repair pathways.

Researchers enrolled 38 patients with incurable solid tumors and adequate organ function. They assigned patients to treatment with sapacitabine twice daily for seven days followed by seliciclib twice daily for three days.

Four patients with BRCA-deficient pancreatic, breast or ovarian cancers had confirmed ongoing partial responses to the drug combination. Three patients are experiencing partial responses, with the longest lasting more than 78 weeks.

Furthermore, researchers observed stable disease of 12 weeks or more in eight additional patients, including two patients with ovarian and breast cancers who carried the BRCA mutation and whose stable disease lasted 64 weeks and 21 weeks, respectively.

The maximum tolerated doses were 50 mg sapacitabine twice daily and 1,200 mg seliciclib twice daily. Dose-limiting toxicities included reversible transaminase elevations and neutropenia. Adverse events were mild to moderate in intensity.

Results of skin biopsies after treatment showed a 2.3-fold increase in DNA damage induced by sapacitabine, as measured by gamma-H2AX immunohistochemistry. Additional DNA damage occurred after treatment with seliciclib with a 0.58-fold further increase in gamma-H2AX staining.

“Initially in the dose-escalation phase of the trial, this combination produced stable disease of modest duration in some patients, which has been the experience with sapacitabine and CDK inhibitors in solid tumors,” Shapiro said. “However, other published research during the course of the study indicated the role of the homologous recombination pathway, dependent on BRCA proteins, for repair of sapacitabine-induced DNA damage. Additionally, the CDK proteins were implicated in DNA repair pathways. These findings prompted us to enroll patients with advanced cancer who had the BRCA mutation and led to the first partial responses and instances of durable stable disease.”

Based on these emerging results, Shapiro and colleagues continue to enroll appropriate patients in the trial, where the combination has been most efficacious. Additional schedules of the combination therapy are under evaluation. According to Shapiro, if further work continues to confirm BRCA mutation status as a potential biomarker for response, these drugs, both individually and in combination, should ultimately be evaluated in larger groups of patients who carry BRCA mutation. If successful, these drugs may provide an important treatment alternative for patients with BRCA-deficient cancers.

FDA approves Olaparib - Lynparza to treat advanced ovarian cancer First LDT companion diagnostic test also approved to identify appropriate patients

Source: FDA - Federal Food and Drug Administration

The U.S. Food and Drug Administration today granted accelerated approval to Lynparza (olaparib), a new drug treatment for women with advanced ovarian cancer associated with defective BRCA genes, as detected by an FDA-approved test.

Ovarian cancer forms in the ovary, one of a pair of female reproductive glands where ova, or eggs, are formed. The National Cancer Institute estimates that 21,980 American women will be diagnosed with and 14,270 will die from ovarian cancer in 2014.

Lynparza is a poly ADP-ribose polymerase (PARP) inhibitor that blocks enzymes involved in repairing damaged DNA. It is intended for women with heavily pretreated ovarian cancer that is associated with defective BRCA genes.

“Today’s approval constitutes the first of a new class of drugs for treating ovarian cancer,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Lynparza is approved for patients with specific abnormalities in the BRCA gene and is an example of how a greater understanding of the underlying mechanisms of disease can lead to targeted, more personalized treatment.

The FDA approved Lynparza with a genetic test called BRACAnalysis CDx, a companion diagnostic that will detect the presence of mutations in the BRCA genes (gBRCAm) in blood samples from patients with ovarian cancer. The BRCA genes are involved with repairing damaged DNA and normally work to suppress tumor growth. Women with mutations resulting in defective BRCA genes are more likely to get ovarian cancer, and it is estimated that 10 to 15 percent of all ovarian cancer is associated with these hereditary BRCA mutations.

The FDA evaluated the BRACAnalysis CDx’s safety and efficacy under the agency’s premarket approval pathway used for high-risk medical devices. Until now, the manufacturer, a clinical laboratory, had been marketing this test, although not specifically for use as a companion diagnostic, without FDA approval as a laboratory developed test (LDT), which is a test that is designed, manufactured and used in a single laboratory. The new test is approved as a companion diagnostic, specifically to identify patients with advanced ovarian cancer who may be candidates for treatment with Lynparza.

“The approval of safe and effective companion diagnostic tests and drugs continue to be important developments in oncology,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health. “We are very excited that the BRACAnalysis CDx is the FDA’s first approval of an LDT under a premarket approval application and is the first approval of an LDT companion diagnostic. The use of companion diagnostics helps bring to market safe and effective treatments specific to a patient’s needs.”

The FDA’s approval of the BRACAnalysis CDx is based on data from the clinical study used to support approval of Lynparza. Blood samples from clinical trial participants were tested to validate the test’s use for detecting BRCAmutations in this population.

Lynparza’s efficacy was examined in a study where 137 participants with gBRCAm-associated ovarian cancer received the drug. The study was designed to measure objective response rate (ORR), or the percentage of participants who experienced partial shrinkage or complete disappearance of the tumor. Results showed 34 percent of participants experienced ORR for an average of 7.9 months.

Common side effects of Lynparza included nausea, fatigue, vomiting, diarrhea, distorted taste (dysgeusia), indigestion (dyspepsia), headache, decreased appetite, common cold-like symptoms (nasopharyngitis), cough, joint paint (arthralgia), musculoskeletal pain, muscle pain (myalgia), back pain, rash (dermatitis) and abdominal pain. Serious side effects included the development of myelodysplastic syndrome, a condition where the bone marrow is unable to produce enough functioning blood cells; acute myeloid leukemia, a bone marrow cancer; and lung inflammation.

The most common laboratory abnormalities were increased creatinine, increased average volume of red blood cells (mean corpuscular volume elevation), decreased red blood cell count (hemoglobin), decreased white blood cell count (lymphocytes and neutrophils) and decreased platelet levels.

In June, Lynparza was reviewed by the FDA’s Oncologic Drugs Advisory Committee for potential use as maintenance therapy (treatment given to keep cancer from returning). The committee advised the agency in a vote of 11 to 2 that the data did not support Lynparza’s accelerated approval for this use. After the meeting, the company submitted additional information supporting Lynparza’s use for a different use: in patients with gBRCAm-associated ovarian cancer who have received three or more chemotherapy treatments.

The FDA is approving Lynparza under the agency’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials. Lynparza’s application was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that are intended to treat a serious disease or condition and, if approved, would offer significant improvement compared to marketed products.

BRACAnalysis CDx’s application was reviewed under the FDA’s priority review program for devices, which provides for priority review of devices that meet certain criteria, including that the devices are intended to treat or diagnose a life-threatening or irreversibly debilitating disease or condition and, if approved, would offer significant, clinically meaningful advantages compared to marketed products.

Lynparza is marketed by AstraZeneca Pharmaceuticals, based in Wilmington, Delaware. BRACAnalysis CDx is manufactured by and performed at Salt Lake City, Utah-based Myriad Genetic Laboratories, Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, promotes and protects the public health by, among other things, assuring the safety, effectiveness and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Lynparza™approved in the European Union as first-in-class treatment for advanced BRCA-mutated ovarian cancer

Source: Astrazeneca:

Thursday, 18 December 2014

AstraZeneca today announced that the European Commission (EC) has granted Marketing Authorisation for Lynparza™ (olaparib) capsules (400mg twice daily) as the first therapy for the maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic) high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete response or partial response to platinum-based chemotherapy.

Olaparib is a poly ADP-ribose polymerase (PARP) inhibitor that exploits tumour DNA repair pathway deficiencies to preferentially kill cancer cells. It is the first PARP inhibitor to be approved for patients with platinum-sensitive relapsed BRCA-mutated ovarian cancer. Patients will be identified through a validated diagnostic test.

“We are delighted to be able to bring this much needed treatment to patients with BRCA-mutated ovarian cancer whose options are currently very limited. Today’s approval marks a significant milestone in the development of the next generation of targeted medicines,” said Briggs Morrison, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca. “We are committed to bringing new treatments to the patients who need them most and today’s news marks only the first of what we hope will be a number of indications in which Lynparza has the potential to transform the lives of cancer patients, including those with breast, pancreatic and gastric cancers.”

The EC decision is applicable to all 28 EU member states as well as Norway, Iceland and Liechtenstein. The approval of olaparib was based on data from Study 19¹, a Phase II clinical trial that evaluated its efficacy and safety compared to placebo in platinum-sensitive relapsed high grade serous ovarian cancer patients. The study showed that olaparib maintenance therapy significantly prolonged progression free survival (PFS) compared with placebo in patients with BRCA-mutated ovarian cancer: median PFS 11.2 months vs 4.3 months (PFS Hazard Ratio = 0.18; 95% Confidence Interval 0.10-0.31; p<0.0001). The most common adverse events associated with olaparib monotherapy to date were generally mild to moderate and included nausea, vomiting, fatigue and anaemia.

Professor Steve Jackson, scientist at the University of Cambridge, whose research established the basis for olaparib and its clinical potential said: "It is wonderful to learn that olaparib is set to become a licensed drug and will therefore soon become available to advanced ovarian cancer sufferers. I also look forward to learning the results of ongoing trials exploring olaparib's potential for the treatment of other cancers. Today's announcement highlights how, by collaborating with a partner such as AstraZeneca, basic academic research, such as that carried out by the research team at the University of Cambridge, can lead to major medical developments."

“It is fantastic news that Lynparza will now be available for women with advanced relapsed BRCA-mutated ovarian cancer,” said Dr John Green, Senior Lecturer, Institute of Translational Medicine, University of Liverpool and Chair, European Network of Gynaecological Cancer Advocacy Groups (ENGAGe). “This is a devastating disease which has a profound impact on patients and their families. Women with a BRCA mutation are especially at risk and there has been a significant need for new treatment options with novel modes of action. The development of a targeted treatment like Lynparza is an excellent example of pioneering research being translated into a treatment that has the potential to transform the lives of patients.”

NOTES TO EDITORS

¹Ledermann J et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncology. 2014. 15:852-861.

Additional commentary

Harpal Kumar, chief executive of Cancer Research UK, said: “It’s great news that the European Commission has approved the use of olaparib within the European Union, especially when Cancer Research UK scientists played a crucial role in discovering and developing this new generation of cancer drugs. This drug offers new hope to women with advanced ovarian cancer by targeting the weaknesses cancer cells have in repairing damaged DNA. With clinical trial results showing this treatment has potential in other types of cancer, we hope there will be more good news in the future. Our partnerships with AstraZeneca are helping us to bring more new treatments to patients, accelerating our efforts to beat cancer sooner."

About Lynparza™ (olaparib)

Olaparib is an innovative, first-in-class oral poly ADP-ribose polymerase (PARP) inhibitor that exploits tumour DNA repair pathways deficiencies to preferentially kill cancer cells. This mode of action gives olaparib the potential for activity in a range of tumour types with DNA repair deficiencies.

In addition to ovarian cancer, AstraZeneca will investigate the full potential of olaparib in multiple tumour types, with Phase III studies in second line gastric cancer, BRCA-mutated pancreatic cancer and adjuvant and metastatic BRCA-mutated breast cancers underway.

About ovarian cancer

In Europe, ovarian cancer is the fifth most commonly diagnosed cancer in women and the sixth leading cause of cancer death among women, mainly because it is often diagnosed late by which time the patient has an extremely poor prognosis. For the 61% of ovarian cancer patients whose cancer has metastasised by the time of diagnosis, the five-year survival rate is only 27%.

Up to 15% of women with ovarian cancer have a BRCA mutation, which is the most common cause of homologous repair deficiency. In BRCA-mutated tumour cells, homologous recombination is defective and DNA double-strand break repair is forced to occur via error-prone pathways, which can lead to genomic instability and cell death.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca.com

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