{"id":56358,"date":"2023-04-29T00:03:05","date_gmt":"2023-04-28T22:03:05","guid":{"rendered":"https:\/\/pharma-trend.com\/en\/update-on-fda-advisory-committee-vote-on-lynparza-olaparib-plus-abiraterone-and-prednisone-or-prednisolone-in-first-line-metastatic-castration-resistant-prostate-cancer\/"},"modified":"2023-04-29T00:03:05","modified_gmt":"2023-04-28T22:03:05","slug":"update-on-fda-advisory-committee-vote-on-lynparza-olaparib-plus-abiraterone-and-prednisone-or-prednisolone-in-first-line-metastatic-castration-resistant-prostate-cancer","status":"publish","type":"post","link":"https:\/\/pharma-trend.com\/en\/update-on-fda-advisory-committee-vote-on-lynparza-olaparib-plus-abiraterone-and-prednisone-or-prednisolone-in-first-line-metastatic-castration-resistant-prostate-cancer\/","title":{"rendered":"Update on FDA Advisory Committee Vote on LYNPARZA\u00ae (olaparib) Plus Abiraterone and Prednisone or Prednisolone in First-Line Metastatic Castration-Resistant Prostate Cancer"},"content":{"rendered":"
\n

RAHWAY, N.J.–(BUSINESS WIRE)–$MRK<\/a> #MRK<\/a>–Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the U.S. Food and Drug Administration\u2019s (FDA) Oncologic Drugs Advisory Committee (ODAC), by a vote of 11 to 1 with one abstention, supported FDA approval of LYNPARZA plus abiraterone and prednisone or prednisolone (abi\/pred) for the first-line treatment of adult patients with BRCA<\/i>-mutated (BRCA<\/i>m) metastatic castration-resistant prostate cancer (mCRPC). The committee voted that FDA should restrict use of LYNPARZA plus abi\/pred to these BRCA<\/i>m mCRPC patients, recommending against approval beyond this patient population.<\/p>\n

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

\nIn August 2022, the FDA accepted the supplemental New Drug Application for LYNPARZA plus abi\/pred for priority review based on positive results from the pivotal Phase 3 PROpel trial, which were also published in NEJM Evidence<\/i>. The ODAC provides the FDA with independent, expert advice and recommendations on marketed and investigational medicines for use in the treatment of cancer. The FDA is not bound by the committee\u2019s guidance but takes its advice into consideration. AstraZeneca and Merck will continue to work with the FDA as the agency completes its review of the application.<\/p>\n

\nNeal Shore, chief medical officer of urology and surgical oncology for GenesisCare, US and PROpel trial investigator, said, \u201cToday\u2019s recommendation by the ODAC is disappointing news for clinicians and prostate cancer patients alike. Preventing or delaying radiographic progression is an important clinical endpoint in assessing oncologic treatment and is very relevant to patients, their caregivers and their families. It is essential that physicians and their patients have an opportunity to choose treatment with the goal of optimizing cancer care outcomes.\u201d<\/p>\n

\nSusan Galbraith, executive vice president, oncology R&D, AstraZeneca, said, \u201cNovel treatments are urgently needed for patients with metastatic castration-resistant prostate cancer. While we are pleased with the recognition of the benefit of LYNPARZA plus abiraterone for patients with BRCA<\/i>-mutated metastatic castration-resistant prostate cancer, we are disappointed with the outcome of today\u2019s ODAC meeting. We strongly believe in the results of the PROpel trial, which demonstrated a clinically meaningful benefit for this combination in a broad population of patients regardless of biomarker status.\u201d<\/p>\n

\nEliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories, said, \u201cWith the incidence and mortality of prostate cancer set to double in the coming decades, it is critical that we bring new treatment options with the potential to reduce the risk of disease progression or death to patients at the earliest possible moment in their care. Though we are pleased that the ODAC recommended LYNPARZA for patients with mCRPC who have BRCA<\/i> mutations, we believe in the potential of LYNPARZA plus abi\/pred for a broad range of patients with mCRPC, based on the results of PROpel. We look forward to the outcome of the FDA\u2019s review of the application.\u201d<\/p>\n

\nResults from the PROpel trial showed a statistically significant and clinically meaningful 34% reduction in the risk of radiographic disease progression or death with LYNPARZA plus abi\/pred (HR=0.66 [95% CI, 0.54-0.81]; p<0.001) versus placebo plus abi\/pred in patients with mCRPC. Median radiographic progression-free survival (rPFS) was 24.8 months versus 16.6 months, respectively.<\/p>\n

\nFurther results from the final pre-specified overall survival (OS) analysis were presented at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium (maturity 47.9%, HR=0.81 [95% CI, 0.67-1.00]; p=0.0544). While the observed 7.4-month numerical increase in median OS did not achieve statistical significance, the totality of the efficacy results from PROpel build on the meaningful gains achieved for patients in this setting versus patients treated with abi\/pred alone, a current standard of care.<\/p>\n

\nIn exploratory analyses of the BRCA<\/i>m subgroup, patients in the LYNPARZA plus abi\/pred arm had fewer rPFS (HR=0.23 [95% CI, 0.12-0.43]) and OS (HR=0.29 [95% CI, 0.14-0.56]) events versus those receiving placebo plus abi\/pred. In the subgroup of patients who tested negative for BRCAm by either a tumor tissue-based test or a circulating tumor DNA test, patients in the LYNPARZA plus abi\/pred arm also had fewer rPFS events (HR=0.76 [95% CI, 0.61-0.94] versus those receiving placebo plus abi\/pred, as well as modestly fewer OS events (HR=0.91 [95% CI, 0.73-1.13]).<\/p>\n

\nThe safety and tolerability of LYNPARZA plus abi\/pred in PROpel was in line with that observed in prior clinical trials and the known profiles of the individual medicines. <\/b>The most common adverse events (AEs) (\u226520%) were anemia (49.7%), fatigue (38.7%), nausea (30.7%), back pain (21.6%) and diarrhea (20.6%). Grade \u22653 AEs were anemia (16.1%), hypertension (3.8%), urinary tract infection (2.5%), fatigue (2.5%), vomiting (1.5%), diarrhea (1.3%), decreased appetite (1%), back pain (1%) and nausea (0.3%). Approximately 17% of patients who received LYNPARZA in combination with abi\/pred discontinued treatment due to an AE.<\/p>\n

\nLYNPARZA in combination with abi\/pred is approved in the European Union and several other countries for the treatment of adult patients with mCRPC based on the PROpel trial. In the U.S., LYNPARZA is currently approved for patients with homologous recombination repair gene-mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone based on the Phase 3 PROfound trial. For that U.S. indication, patients are selected for therapy based on an FDA-approved companion diagnostic for LYNPARZA.<\/p>\n

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

\nPROpel is a randomized, double-blind Phase 3 trial testing the efficacy, safety and tolerability of LYNPARZA <\/i>versus placebo when given in addition to abi\/pred in patients with mCRPC who had not received prior chemotherapy or new hormonal agents in the mCRPC setting. The major efficacy outcome was rPFS as assessed by investigator per RECIST v1.1 and Prostate Cancer Working Group (bone) criteria. OS was an additional efficacy outcome measure.<\/p>\n

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

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

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

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

\nVenous Thromboembolic Events (VTE):<\/b> Including severe or fatal pulmonary embolism (PE) occurred in patients treated with LYNPARZA. VTE 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.<\/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.<\/p>\n

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

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

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

\nMost common laboratory abnormalities (Grades 1-4) in \u226525% of patients who received LYNPARZA in the first-line maintenance setting <\/b>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%).<\/p>\n

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

\nMost common adverse reactions (Grades 1-4) in \u226510% of patients treated with LYNPARZA\/bevacizumab and at a \u22655% frequency compared to 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%).<\/p>\n

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

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

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

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

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

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

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

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

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

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

\nINDICATIONS<\/b><\/p>\n

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

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

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