{"id":47327,"date":"2022-08-16T13:01:47","date_gmt":"2022-08-16T11:01:47","guid":{"rendered":"https:\/\/pharma-trend.com\/en\/fda-accepts-submission-of-supplemental-new-drug-application-for-lynparza-olaparib-in-combination-with-abiraterone-and-prednisone-or-prednisolone-for-patients-with-metastatic-castration-resista\/"},"modified":"2022-08-16T13:01:47","modified_gmt":"2022-08-16T11:01:47","slug":"fda-accepts-submission-of-supplemental-new-drug-application-for-lynparza-olaparib-in-combination-with-abiraterone-and-prednisone-or-prednisolone-for-patients-with-metastatic-castration-resista","status":"publish","type":"post","link":"https:\/\/pharma-trend.com\/en\/fda-accepts-submission-of-supplemental-new-drug-application-for-lynparza-olaparib-in-combination-with-abiraterone-and-prednisone-or-prednisolone-for-patients-with-metastatic-castration-resista\/","title":{"rendered":"FDA Accepts Submission of Supplemental New Drug Application for LYNPARZA\u00ae (olaparib) in Combination With Abiraterone and Prednisone or Prednisolone for Patients With Metastatic Castration-Resistant Prostate Cancer and Grants Priority Review"},"content":{"rendered":"
\n

\nFirst PARP inhibitor to demonstrate clinical benefit in radiographic progression-free survival in combination with a new hormonal agent with or without homologous recombination repair gene<\/b> mutations<\/b>\n<\/p>\n

RAHWAY, N.J.–(BUSINESS WIRE)–$MRK<\/a> #MRK<\/a>–AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that a supplemental New Drug Application (sNDA) 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 (FDA) for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC). The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date in the fourth quarter of 2022.\n<\/p>\n

<\/a><\/p>\n

\nIn 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 (CRPC) 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.\n<\/p>\n

\nSusan Galbraith, executive vice president, oncology R&D, AstraZeneca, said, \u201cThere remains a critical unmet need among patients diagnosed with mCRPC, where the prognosis remains poor, and treatment options are limited. Today\u2019s 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.\u201d\n<\/p>\n

\nDr. Eliav Barr, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, \u201cMerck is committed to developing new treatment options for patients with mCRPC, a complex disease that urgently needs more therapies. We look forward to working with the FDA towards the goal of bringing a new option to patients with mCRPC with or without homologous recombination repair gene mutations.\u201d\n<\/p>\n

\nThe sNDA was based on results from the Phase 3 PROpel trial, which were presented at the 2022 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium and later published in NEJM<\/i> Evidence.<\/i>\n<\/p>\n

\nIn PROpel, LYNPARZA in combination with abiraterone and prednisone or prednisolone reduced the risk of disease progression or death by 34% (HR=0.66 [95% CI, 0.54-0.81]; p<0.0001) versus placebo plus abiraterone and prednisone or prednisolone. Median radiographic progression-free survival (rPFS) was 24.8 months for the LYNPARZA <\/i>plus abiraterone arm versus 16.6 months for the placebo plus abiraterone arm.\n<\/p>\n

\nThe safety and tolerability of LYNPARZA in combination with abiraterone and prednisone or prednisolone was in line with that observed in prior clinical trials and the known profiles of the individual medicines. The most common adverse events (AEs) (\u226520%) were anemia (46%), fatigue (37%) and nausea (28%). Grade \u22653 AEs were anemia (15%), hypertension (4%), urinary tract infection (2%), fatigue (2%), decreased appetite (1%), vomiting (1%), back pain (1%), diarrhea (1%) and nausea (0.3%). Approximately 14% of patients who received LYNPARZA in combination with abiraterone and prednisone or prednisolone discontinued treatment due to an AE.\n<\/p>\n

\nLYNPARZA <\/i>is approved in the U.S. for patients with homologous recombination repair (HRR) gene-mutated mCRPC (BRCA<\/i>-mutated and certain other HRR gene mutations) who have progressed following prior treatment with enzalutamide or abiraterone and in the European Union, Japan and China for patients with BRCA<\/i>-mutated mCRPC who have progressed following prior therapy that included a new hormonal agent (NHA).\n<\/p>\n

\nAbout PROpel<\/b>\n<\/p>\n

\nPROpel (ClinicalTrials.gov, NCT03732820<\/a>) is a randomized, double-blind Phase 3 trial testing the efficacy safety, and tolerability of LYNPARZA versus placebo when given in addition to abiraterone and prednisone or prednisolone in patients with mCRPC who had not received prior chemotherapy or NHAs in the mCRPC setting. The primary endpoint is rPFS, and secondary endpoints include overall survival, time to secondary progression or death and time to first subsequent therapy.\n<\/p>\n

\nIMPORTANT SAFETY INFORMATION<\/b>\n<\/p>\n

\nCONTRAINDICATIONS<\/b>\n<\/p>\n

\nThere are no contraindications for LYNPARZA.\n<\/p>\n

\nWARNINGS AND PRECAUTIONS<\/b>\n<\/p>\n

\nMyelodysplastic Syndrome\/Acute Myeloid Leukemia (MDS\/AML): <\/b>Occurred in approximately 1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The median duration of therapy in patients who developed MDS\/AML was 2 years (range: <6 months to >10 years). All of these patients had previous chemotherapy with platinum agents and\/or other DNA-damaging agents, including radiotherapy.\n<\/p>\n

\nDo not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (\u2264Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.\n<\/p>\n

\nIf the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS\/AML is confirmed.\n<\/p>\n

\nPneumonitis: <\/b>Occurred in 0.8% of patients exposed to LYNPARZA monotherapy, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.\n<\/p>\n

\nEmbryo-Fetal Toxicity: <\/b>Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.\n<\/p>\n

\nFemales<\/i>\n<\/p>\n

\nAdvise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.\n<\/p>\n

\nMales<\/i>\n<\/p>\n

\nAdvise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.\n<\/p>\n

\nVenous Thromboembolic Events:<\/b> Including pulmonary embolism, occurred in 7% of patients with metastatic castration-resistant prostate cancer who received LYNPARZA plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. Patients receiving LYNPARZA and ADT had a 6% incidence of pulmonary embolism compared to 0.8% of patients treated with ADT plus either enzalutamide or abiraterone. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism, and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated.\n<\/p>\n

\nADVERSE REACTIONS\u2014First-Line Maintenance BRCA<\/i>m Advanced Ovarian Cancer<\/b>\n<\/p>\n

\nMost common adverse reactions (Grades 1-4) in \u226510% of patients who received LYNPARZA in the first-line maintenance setting<\/b> for SOLO-1 <\/b>were: nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection\/influenza\/nasopharyngitis\/bronchitis (28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), urinary tract infection (13%), thrombocytopenia (11%), and stomatitis (11%).\n<\/p>\n

\nMost common laboratory abnormalities (Grades 1-4) in \u226525% of patients who received LYNPARZA in the first-line maintenance setting for SOLO-1<\/b> were: decrease in hemoglobin (87%), increase in mean corpuscular volume (87%), decrease in leukocytes (70%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease in platelets (35%), and increase in serum creatinine (34%).\n<\/p>\n

\nADVERSE REACTIONS\u2014First-Line Maintenance Advanced Ovarian Cancer in Combination with Bevacizumab<\/b>\n<\/p>\n

\nMost common adverse reactions (Grades 1-4) in \u226510% of patients treated with LYNPARZA\/bevacizumab compared to a \u22655% frequency for placebo\/bevacizumab in the first-line maintenance setting<\/b> for PAOLA-1<\/b> were: nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%) and leukopenia (18%). In addition, the most common adverse reactions (\u226510%) for patients receiving LYNPARZA\/bevacizumab irrespective of the frequency compared with the placebo\/bevacizumab arm were: diarrhea (18%), neutropenia (18%), urinary tract infection (15%) and headache (14%).\n<\/p>\n

\nIn addition, venous thromboembolic events occurred more commonly in patients receiving LYNPARZA\/bevacizumab (5%) than in those receiving placebo\/bevacizumab (1.9%).\n<\/p>\n

\nMost common laboratory abnormalities (Grades 1-4) in \u226525% of patients for LYNPARZA in combination with bevacizumab in the first-line maintenance setting<\/b> for PAOLA-1<\/b> were: decrease in hemoglobin (79%), decrease in lymphocytes (63%), increase in serum creatinine (61%), decrease in leukocytes (59%), decrease in absolute neutrophil count (35%) and decrease in platelets (35%).\n<\/p>\n

\nADVERSE REACTIONS\u2014Maintenance Recurrent Ovarian Cancer<\/b>\n<\/p>\n

\nMost common adverse reactions (Grades 1-4) in \u226520% of patients who received LYNPARZA in the maintenance setting <\/b>for SOLO-2<\/b> were: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis\/upper respiratory tract infection (URI)\/influenza (36%), diarrhea (33%), arthralgia\/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%).\n<\/p>\n

\nStudy 19: <\/b>nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), decreased appetite (21%) and dyspepsia (20%).\n<\/p>\n

\nMost common laboratory abnormalities (Grades 1-4) in \u226525% of patients who received LYNPARZA in the maintenance setting (SOLO-2\/Study 19<\/b>) were: increase in mean corpuscular volume (89%\/82%), decrease in hemoglobin (83%\/82%), decrease in leukocytes (69%\/58%), decrease in lymphocytes (67%\/52%), decrease in absolute neutrophil count (51%\/47%), increase in serum creatinine (44%\/45%), and decrease in platelets (42%\/36%).\n<\/p>\n

\nADVERSE REACTIONS\u2014Advanced gBRCA<\/i>m Ovarian Cancer After 3 or More Lines of Chemotherapy<\/b>\n<\/p>\n

\nMost common adverse reactions (Grades 1-4) in \u226520% of patients who received\n<\/p>\n

\nLYNPARZA for advanced gBRCA<\/i>m ovarian cancer after 3 or more lines of chemotherapy <\/b>(pooled from 6 studies) were: fatigue\/asthenia (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis\/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia\/musculoskeletal pain (21%).\n<\/p>\n

\nMost common laboratory abnormalities (Grades 1-4) in \u226525% of patients who received LYNPARZA for advanced gBRCA<\/i>m ovarian cancer <\/b>(pooled from 6 studies) were: decrease in hemoglobin (90%), mean corpuscular volume elevation (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).\n<\/p>\n

\nADVERSE REACTIONS\u2014Adjuvant Treatment of gBRCA<\/i>m, HER2-Negative, High-Risk Early Breast Cancer<\/b>\n<\/p>\n

\nMost common adverse reactions (Grades 1-4) in \u226510% of patients who received LYNPARZA in the adjuvant setting<\/b> for OlympiA<\/b> were: nausea (57%), fatigue (including asthenia) (42%), anemia (24%), vomiting (23%), headache (20%), diarrhea (18%), leukopenia (17%), neutropenia (16%), decreased appetite (13%), dysgeusia (12%), dizziness (11%), and stomatitis (10%).\n<\/p>\n

\nMost common laboratory abnormalities (Grades 1-4) in \u226525% of patients who received LYNPARZA in the adjuvant setting <\/b>for OlympiA<\/b> were: decrease in lymphocytes (77%), increase in mean corpuscular volume (67%), decrease in hemoglobin (65%), decrease in leukocytes (64%), and decrease in absolute neutrophil count (39%).\n<\/p>\n

\nADVERSE REACTIONS\u2014gBRCA<\/i>m, HER2-Negative Metastatic Breast Cancer<\/b>\n<\/p>\n

\nMost common adverse reactions (Grades 1-4) in \u226520% of patients who received LYNPARZA in the metastatic setting<\/b> for OlympiAD<\/b> were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).\n<\/p>\n

\nMost common laboratory abnormalities (Grades 1-4) in ><\/span>25% of patients who received LYNPARZA in the metastatic setting<\/b> for OlympiAD <\/b>were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).\n<\/p>\n

\nADVERSE REACTIONS\u2014First-Line Maintenance gBRCA<\/i>m Metastatic Pancreatic Adenocarcinoma<\/b>\n<\/p>\n

\nMost common adverse reactions (Grades 1-4) in \u226510% of patients who received LYNPARZA in the first-line maintenance setting<\/b> for POLO <\/b>were: fatigue (60%), nausea (45%), abdominal pain (34%), diarrhea (29%), anemia (27%), decreased appetite (25%), constipation (23%), vomiting (20%), back pain (19%), arthralgia (15%), rash (15%), thrombocytopenia (14%), dyspnea (13%), neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and stomatitis (10%).\n<\/p>\n

\nMost common laboratory abnormalities (Grades 1-4) in \u226525% of patients who received LYNPARZA in the first-line maintenance setting<\/b> for POLO<\/b> were: increase in serum creatinine (99%), decrease in hemoglobin (86%), increase in mean corpuscular volume (71%), decrease in lymphocytes (61%), decrease in platelets (56%), decrease in leukocytes (50%), and decrease in absolute neutrophil count (25%).\n<\/p>\n

\nADVERSE REACTIONS\u2014HRR Gene-mutated Metastatic Castration Resistant Prostate Cancer<\/b>\n<\/p>\n

\nMost common adverse reactions (Grades 1-4) in \u226510% of patients who received LYNPARZA for PROfound<\/b> were: anemia (46%), fatigue (including asthenia) (41%), nausea (41%), decreased appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia (12%), cough (11%), and dyspnea (10%).\n<\/p>\n

\nMost common laboratory abnormalities (Grades 1-4) in \u226525% of patients who received LYNPARZA for PROfound<\/b> were: decrease in hemoglobin (98%), decrease in lymphocytes (62%), decrease in leukocytes (53%), and decrease in absolute neutrophil count (34%).\n<\/p>\n

\nDRUG INTERACTIONS<\/b>\n<\/p>\n

\nAnticancer Agents: <\/b>Clinical studies of LYNPARZA with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.\n<\/p>\n

\nCYP3A Inhibitors: <\/b>Avoid coadministration of strong or moderate CYP3A inhibitors when using LYNPARZA. If a strong or moderate CYP3A inhibitor must be coadministered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.\n<\/p>\n

\nCYP3A Inducers: <\/b>Avoid coadministration of strong or moderate CYP3A inducers when using LYNPARZA.\n<\/p>\n

\nUSE IN SPECIFIC POPULATIONS<\/b>\n<\/p>\n

\nLactation: <\/b>No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.\n<\/p>\n

\nPediatric Use: <\/b>The safety and efficacy of LYNPARZA have not been established in pediatric patients.\n<\/p>\n

\nHepatic Impairment: <\/b>No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C).\n<\/p>\n

\nRenal Impairment: <\/b>No dosage modification is recommended in patients with mild renal impairment (CLcr 51-80 mL\/min estimated by Cockcroft-Gault). In patients with moderate renal impairment (CLcr 31-50 mL\/min), reduce the dose of LYNPARZA to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr \u226430 mL\/min).\n<\/p>\n

\nINDICATIONS for LYNPARZA in the United States<\/b>\n<\/p>\n

\nLYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for:\n<\/p>\n

\nFirst-Line Maintenance BRCA<\/i>m Advanced Ovarian Cancer<\/b>\n<\/p>\n

\nFor the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA<\/i>-mutated (gBRCA<\/i>m or sBRCA<\/i>m) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.\n<\/p>\n

\nFirst-Line Maintenance HRD-Positive Advanced Ovarian Cancer in Combination with Bevacizumab<\/b>\n<\/p>\n

\nIn combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either:\n<\/p>\n