Could You Provide An Overview Of Parp Inhibitors How Do They Work
PARP inhibitors work on a principle called synthetic lethality. Briefly, PARP inhibitors increase the amount of DNA damage in the cancer cell. As a general principle, a little bit of DNA damage is a good thing for a cancer cell it helps it survive and metastasize and grow more rapidly and proliferate. But too much DNA damage can be a bad thing because it can lead to catastrophic genomic instability and subsequent cancer cell death.
PARP inhibitors work best in cancers that have mutations in homologous recombination repair genes. The most well-known of these in prostate cancer is BRCA2. BRCA2 is a gene that is responsible for fixing double-strand DNA breaks. There is another way that cancer cells can fix DNA breaks, which is called single-strand repair, fixing 1 DNA strand at a time. So if you have a patient with a BRCA2 mutation, that cancer cells ability to fix double-strand DNA breaks is impaired. It then relies on the other pathway, the single-strand repair pathway, to fix its DNA damage. That single-strand repair pathway is done by an enzyme called PARP, primarily PARP1. If PARP1 is inhibited by a drug, such as a PARP inhibitor, in a patient who already has a mutation in the alternative mechanism of DNA repairin other words, BRCA2then that cancer cell develops catastrophic DNA damage, so that the next time it replicates its not able to survive and it dies.
Adverse Reactionsmaintenance Recurrent Ovariancancer
Most common adverse reactions in 20% of patients who received LYNPARZA in the maintenance setting for SOLO-2 were: nausea, fatigue ,anemia , vomiting ,nasopharyngitis/upper respiratory tract infection /influenza ,diarrhea , arthralgia/myalgia ,dysgeusia , headache , decreasedappetite , and stomatitis .
Study 19: nausea , fatigue , vomiting , diarrhea , anemia , respiratory tract infection, constipation , headache , decreased appetite , and dyspepsia.
Most common laboratory abnormalities in 25% of patients who received LYNPARZA in the maintenance setting were:increase in mean corpuscular volume , decrease in hemoglobin , decrease in leukocytes ,decrease in lymphocytes , decrease in absolute neutrophil count , increase in serum creatinine ,and decrease in platelets .
What Genetic Testing Is Needed To Determine A Patients Eligibility For Treatment With A Parp Inhibitor
Patients with prostate cancer who are eligible for treatment with a PARP inhibitor have to have either a germline or somatic mutation in 1 or more of the DNA repair genes. In the case of olaparib, the range of genes is more expansive and includes 14 genes, including but not limited to BRCA1, BRCA2, ATM, CHEK2, PALB2, and CDK12. There are a few others as well. However, in the case of rucaparib, the treatment is restricted to patients who have either germline or somatic BRCA1 or BRCA2 mutations only. At this time, rucaparib cannot be recommended for patients with non-BRCA mutations.
Germline genetic tests can be done using saliva or peripheral blood leukocytes. Somatic genetic testing requires a tumor sample, either a metastatic tumor biopsy or an archival primary prostatic biopsy. In addition, there are now several commercial circulating tumor DNA assays that can assess tumor DNA using a blood test.
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Fda Accepts Submission Of Supplemental New Drug Application For Lynparza In Combination With Abiraterone And Prednisone Or Prednisolone For Patients With Metastatic Castration
First PARP inhibitor to demonstrate clinical benefit in radiographic progression-free survival in combination with a new hormonal agent with or without homologous recombination repair genemutations
RAHWAY, N.J.—-AstraZeneca and Merck , known as MSD outside the United States and Canada, today announced that a supplemental New Drug Application for LYNPARZA in combination with abiraterone and prednisone or prednisolone has been accepted and granted priority review by the U.S. Food and Drug Administration for the treatment of adult patients with metastatic castration-resistant prostate cancer . The FDA has set a Prescription Drug User Fee Act , or target action, date in the fourth quarter of 2022.
In the U.S., prostate cancer is the second most common cancer in male patients. Approximately 10-20% of male patients with advanced prostate cancer are estimated to develop castration resistant prostate cancer within five years, and at least 84% of these men may develop metastases at the time of CRPC diagnosis. Patients with advanced prostate cancer have a particularly poor prognosis, and the five-year survival rate remains low.
The sNDA was based on results from the Phase 3 PROpel trial, which were presented at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium and later published in NEJMEvidence.
About PROpel
IMPORTANT SAFETY INFORMATION
There are no contraindications for LYNPARZA.
WARNINGS AND PRECAUTIONS
Females
Males
Adverse Reactionsmaintenance Recurrent Ovarian Cancer
Most common adverse reactions in 20% of patients who received LYNPARZA in the maintenance setting for SOLO-2 were: nausea ,fatigue , anemia , vomiting , nasopharyngitis/upper respiratory tractinfection /influenza , diarrhea , arthralgia/myalgia , dysgeusia , headache ,decreased appetite , and stomatitis .
Study 19: nausea , fatigue , vomiting ,diarrhea , anemia , respiratory tract infection , constipation , headache , decreasedappetite , and dyspepsia .
Most common laboratory abnormalities in 25% of patients who received LYNPARZA in the maintenance setting were: increasein mean corpuscular volume , decrease in hemoglobin , decrease in leukocytes ,decrease in lymphocytes , decrease in absolute neutrophil count , increase in serumcreatinine , and decrease in platelets .
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Olaparib Tolerability And Common Adverse
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- The safety profile of olaparib in men with mCRPC was similar to other solid tumours.
- Events of anaemia, nausea, decreased appetite and fatigue occurred most frequently.
- Incidences of all four events peaked within the first 2 months of starting treatment.
- All four were generally manageable through dose modifications and supportive therapies.
- Baseline bone metastases or prior taxane use was unrelated to the rate of anaemia.
Fda Grants Priority Review To Olaparib/abiraterone Regimen In Metastatic Castration
The FDA has granted priority review to a supplemental new drug application seeking the approval of olaparib in combination with abiraterone acetate and prednisone or prednisolone in adult patients with metastatic castration-resistant prostate cancer.
The FDA has granted priority review to a supplemental new drug application seeking the approval of olaparib in combination with abiraterone acetate and prednisone or prednisolone in adult patients with metastatic castration-resistant prostate cancer .1
The application is supported by findings from the phase 3 PROpel trial , in which the olaparib plus abiraterone and prednisone or prednisolone significantly prolonged imaging-based progression-free survival vs placebo plus abiraterone and prednisone or prednisolone , at 24.8 months vs 16.6 months, respectively .2 These data proved to be consistent with what was observed with blinded independent central review .
Under the Prescription Drug User Fee Act, the regulatory agency is expected to decide on the sNDA in the fourth quarter of 2022.
Stratification factors included distant metastasis type at baseline and by docetaxel treatment at the metastatic stage of disease .
Overall survival served as a key secondary end point, as well as time to first subsequent therapy or death, time to second progression or death , and health-related quality of life. Exploratory end points included objective response rate , prostate-specific antigen response rate, and time to PSA progression.
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Fda Grants Swift Review To Lynparza In First
AstraZeneca and Merck & Cos PARP inhibitor Lynparza is already used to treat prostate cancer associated with a specific genetic mutation, but could see its use broadened if a new marketing application is approved by the FDA.
The US regulator has started a priority review of Lynparza in combination with abiraterone and prednisone or prednisolone as a first-line treatment for metastatic castration-resistant prostate cancer based on the results of the PROpel trial.
The study which included an all-comer population of men with mCRPC showed that Lynparza plus Johnson & Johnsons hormonal therapy Zytiga reduced the risk of disease progression or death by 34% versus Zytiga alone, with radiographic progression-free survival of 24.8 months and 16.6 months, respectively.
Lynparza was approved in 2020 as a second-line therapy for homologous recombination repair gene-mutated mCRPC last year, but extending its label to include non-HRR patients in the frontline setting would dramatically increase the number of patients eligible for treatment.
First approved in 2014, the drug is also used for a range of indications across ovarian, breast, fallopian tube, peritoneal and pancreatic cancers, and remains one of AZs fastest growing oncology therapies, with sales rising 18% to almost $1.3 billion in the first half of this year.
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Fda Grants Priority Review To Olaparib Combination For Mcrpc
Olaparib in combination with abiraterone and prednisone, or prednisolone may soon be an FDA-approved treatment for adult patients with metastatic castration-resistant prostate cancer.
The FDA granted priority review for the supplemental new drug application for olaparib in combination with abiraterone and prednisone or prednisolone for treatment of adult patients with metastatic castration-resistant prostate cancer , according to a press release from AstraZeneca.1
Olaparib is being collaboratively developed by both AstraZeneca and MSD Research Laboratories.
There remains a critical unmet need among patients diagnosed with metastatic castration-resistant prostate cancer, where the prognosis remains poor and treatment options are limited. Todays news is another step towards bringing forward a new, much-needed treatment option in this setting. If approved, Lynparza with abiraterone will become the first combination of a PARP inhibitor and a new hormonal agent for patients with this disease, said Susan Galbraith, executive vice president, Oncology Research and Development, of AstraZeneca, in a press release.
Patients were deemed ineligible if they have a known additional malignancy that has had progression or has required active treatment in the last 5 years, have myelodysplastic syndrome or acute myeloid leukemia, clinically significant cardiovascular disease, uncontrolled hypertension, or a history of uncontrolled pituitary or adrenal dysfunction.2
References:
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Can You Discuss The Next Steps For Parp Inhibitors And Prostate Cancer Including Combination Therapy Trials Of Parp Inhibitors With Immunotherapies Or Androgen Receptor Pathway Inhibitors
There are at least 2 future directions for PARP inhibitor treatments. One is to combine these agents with other standard therapies for metastatic prostate cancer. We have been using drugs such as abiraterone acetate and enzalutamide for almost a decade now. These are natural combination partners with PARP inhibitors. There are a number of pivotal phase 3 studies that could lead to FDA approval of these combinations. For example, there is TALAPRO-2 , a phase 3 randomized study of talazoparib plus enzalutamide versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer.
In addition, there is also the MAGNITUDE trial, a phase 3 randomized study evaluating niraparib plus abiraterone in patients with metastatic castration-resistant prostate cancer. The goal of those studies is to see whether the combination of a PARP inhibitor and a novel hormonal therapy might be successful in genetically-unselected patients in other words, not just patients who might have 1 of these HRR gene mutations.
PARP inhibitors are also being studied in the metastatic hormone-sensitive setting. The recently launched AMPLITUDE trial is a phase 3 randomized study of abiraterone plus niraparib versus abiraterone alone in patients with metastatic hormone-sensitive prostate cancer who have a genetic mutation in 1 of these HRR genes. So that one is a biomarker-selected design.
Parp: Prime Treatment Target For Prostate Cancer
Over the past decade, olaparib and rucaparib have become important treatments for women with ovarian and breast cancer, in whom genetic alterations that affect DNA repair processes are common. Among the most frequent such alterations are those in the BRCA1 and BRCA2 genes.
Its no accident that researchers have identified people who have alterations in BRCA genes as ideal candidates for treatment with PARP inhibitors.
BRCA proteins and some PARP proteins are both integral components of cells response to DNA damage. If that response is already dysfunctional because of BRCA1 or BRCA2 mutations, then researchers reasoned that blocking the activity of PARP proteins could further hamper any chance of repairakin to punching a hole in a tire that already has a slow leak. If the cancer cells cant fix the DNA damage, they will die.
Prostate cancer emerged as another strong candidate for PARP inhibitors after studies suggested that alterations in BRCA1 and BRCA2, as well as other genes involved in a cells ability to respond to DNA damage, may be present in approximately one-quarter of men with the disease. Other studies linked these genetic changes to an increased risk of prostate cancer, as well as more aggressive disease.
Those findings, Dr. Karzai explained, led to a series of clinical trials of PARP inhibitors in men with metastatic prostate cancer, laying the foundation for the new FDA approvals.
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Adverse Reactionsadjuvant Treatment Of Gbrcam Her2
Most common adverse reactions in 10% of patients who received LYNPARZA in the adjuvant setting for OlympiA were: nausea ,fatigue , anemia , vomiting , headache , diarrhea , leukopenia, neutropenia , decreased appetite , dysgeusia , dizziness , and stomatitis .
Most common laboratory abnormalities in 25% of patients who received LYNPARZA in the adjuvant setting for OlympiA were: decrease inlymphocytes , increase in mean corpuscular volume , decrease in hemoglobin , decrease inleukocytes , and decrease in absolute neutrophil count .
Fda Approves Multiple Companion Diagnostics For Olaparib In Hrr+ Mcrpc
The FDA has approved the FoundationOneCDx and BRACAnalysis CDx tests as companion diagnostics to identify patients with metastatic castration-resistant prostate cancer with homologous recombination repair mutations, making them eligible for treatment with the PARP inhibitor olaparib.
The FDA has approved the FoundationOneCDx and BRACAnalysis CDx tests as companion diagnostics to identify patients with metastatic castration-resistant prostate cancer with homologous recombination repair mutations, making them eligible for treatment with the PARP inhibitor olaparib .1,2
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Fda Approves Olaparib For Hrr Gene
The FDA approved olaparib for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer.
The FDA has approved olaparib for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer who have progressed following prior treatment with enzalutamide or abiraterone , according to AstraZeneca and Merck, the joint developers of the agent.1
The FDA recommended a dose of 300 mg of olaparib, taken orally twice daily, with or without food.
Prostate cancer has lagged behind other solid tumors in the era of precision medicine, Maha Hussain, MD, one of the principle investigators of the trial and deputy director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, said in a press release. I am thrilled by the approval of , which now brings a molecularly targeted treatment for this patient population in the US. The PROfound trial was an international effort and I want to thank the patients, their families, the investigators, and their teams involved in making it possible.
Fatal AEs occurred in 4% of patients treated with olaparib. These included pneumonia , cardiopulmonary failure , aspiration pneumonia , septic shock , Budd-Chiari Syndrome , sudden death , and acute cardiac failure .
Making Treatment Choices: Olaparib Or Rucaparib
Often, when multiple drugs are approved for the sameor in this case, a very similaruse, the side effects associated with each drug can help doctors decide which therapy is best for each patient.
Overall, Dr. Sartor explained, there arent notable differences in the types or severity of the side effects caused by olaparib and rucaparib.
And although most patients seem to handle the side effects caused by both drugs relatively well, he continued, they can cause substantial problems, including anemia, severe drops in white blood cell count, nausea, and vomiting.
Dr. Karzai also pointed to the risk of myelodysplastic syndrome, a disorder that affects the formation of blood cells in the bone marrow and that has been seen in a very small percentage of patients treated with PARP inhibitors.
These drugs definitely require close monitoring , Dr. Sartor said.
One potential advantage of rucaparib over olaparib could be the eventual availability of a blood test, called a liquid biopsy, that can identify men with BRCA1 or BRCA2 alterations who are candidates for the drug. This liquid biopsy, called FoundationOne Liquid CDx, is currently being evaluated by FDA and a decision on its approval is expected soon, according to a spokesperson for Foundation Medicine, which manufactures the test.
In addition to tissue quantity, there are also issues with the type of tissue that comes from the biopsy and its quality. There a lot of variables that can make it difficult, she added.
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Top Stories In Advanced Prostate Cancer: Olaparib And Rucaparib Fda Approvals
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Please Discuss The Key Findings From The Triton2 And Profound Clinical Trials Of Rucaparib And Olaparib
In May 2020, there were 2 FDA approvals for PARP inhibitors in prostate cancer within 5 days. The first was rucaparib, a PARP inhibitor approved based on a phase 2 single-arm study without a control group, called TRITON2. The TRITON2 study, in an unprecedented way, led to FDA approval of a drug in prostate cancer without requiring randomization and without having a control group. However, it was an accelerated FDA approval, meaning that full approval by the FDA is contingent upon a positive phase 3 randomized study , which is ongoing.
The second trial, which was the PROfound , were randomized to receive either olaparib or a physicians choice of hormonal therapy. The trial was positive, showing a significant prolongation of radiographic progression-free survival but also overall survival in the patients who had BRCA1, BRCA2, and ATM mutations.
As a prespecified secondary analysis, the trial was also powered to evaluate the overall patient population that included patients with mutations in any of the 15 HRR genes, not just the 3 mentioned above. In that entire study population, there was also a prolongation of radiographic progression-free survival with olaparib compared with placebo. This led the FDA to approve olaparib for not just the BRCA1, BRCA2, and ATM genes, but also various other HRR genes, including CHEK2, PALB2, CDK12, and several others.
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