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Bayer receives FDA approval for Copanlisib in adults with relapsed follicular lymphoma after two prior systemic therapies (for specialized target groups only)

On September 14, 2017 Bayer reported that the U.S. Food and Drug Administration (FDA) has approved copanlisib under the brand name Aliqopa 60 mg vial for injection for the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies (Press release, Bayer, SEP 14, 2017, View Source [SID1234520516]). Accelerated approval was granted for this indication based on overall response rate (ORR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

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Copanlisib is a novel intravenous phosphatidylinositol-3-kinase (PI3K) inhibitor with inhibitory activity predominantly against the PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells. The FDA granted approval under the accelerated approval pathway based on data from the open-label, single-arm Phase II CHRONOS-1 [NCT01660451] trial investigating copanlisib in 104 adult patients with follicular B-cell non-Hodgkin’s lymphoma (NHL) who had relapsed disease following at least two prior systemic therapies.

"The U.S. approval of copanlisib in follicular lymphoma is the first of many milestones we look forward to at Bayer across several new promising compounds in our oncology pipeline," said Robert LaCaze, Executive Vice President and Head of the Oncology Strategic Business Unit at Bayer. "We are pleased that the FDA has recognized the promising results of the CHRONOS-1 trial and look forward to offering this important new treatment option to patients with lymphoma, who currently have a high unmet need for effective therapies."

Follicular lymphoma (FL) is the most common subtype of indolent, or slow-growing, non-Hodgkin’s lymphoma (NHL). Response rates and duration of response decline with each line of therapy, underscoring the need for patients whose disease has already progressed.

Developed by Bayer, copanlisib is the only approved PI3K inhibitor with inhibitory activity predominantly against PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells. It is also the only one to be administered intravenously on an intermittent schedule. Copanlisib will be available in the U.S. market immediately.

The New Drug Application for copanlisib received priority review, which is reserved for medicines that would provide significant improvements in the safety or effectiveness of the treatment of serious conditions. The product was approved under FDA regulations 21 CFR Part 314 Subpart H (accelerated approval). The FDA had previously granted copanlisib fast track designation in FL as well as Orphan Drug designation for the treatment of patients with FL and for the treatment of splenic, nodal, and extranodal subtypes of marginal zone lymphoma.

Efficacy and Safety Data Supporting Copanlisib Approval

The Phase II CHRONOS-1 (ClinicalTrials.gov Identifier: NCT01660451) trial included 104 subjects with follicular B-cell non-Hodgkin’s lymphoma (NHL) who had relapsed disease following at least two prior systemic therapies. In the trial, copanlisib achieved an overall response rate (ORR) of 59% [n=104 (95% CI 49, 68)], with 14% of patients achieving a complete response, and a median duration of response of 12.2 months (0+, 22.6). Tumor response was assessed according to the International Working Group response criteria for malignant lymphoma. The primary endpoint was Independent Review Committee-assessed ORR.

Serious adverse reactions were reported in 44 (26%) patients. The most frequent serious adverse reactions that occurred were pneumonia (8%), pneumonitis (5%), and hyperglycemia (5%). Adverse reactions resulted in dose reduction in 36 (21%) and discontinuation in 27 (16%) patients. The most frequently observed adverse drug reactions (≥20%) in copanlisib-treated patients were: hyperglycemia (54%), leukopenia (36%), diarrhea (36%), decreased general strength and energy (36%), hypertension (35%), neutropenia (32%), nausea (26%), thrombocytopenia (22%), and lower respiratory tract infections (21%). The safety data reflect exposure to copanlisib in 168 adults with follicular lymphoma and other hematologic malignancies treated with copanlisb 60 mg or 0.8 mg/kg equivalent in clinical trials. Patients with small lymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom’s macroglobulinemia and marginal zone lymphoma were also enrolled in the study and included in the safety analysis.

About Follicular Lymphoma (FL)
Follicular lymphoma (FL) is the most common histological subtype of indolent, or slow growing, non-Hodgkin’s lymphoma (NHL) that accounts for 22 percent of all newly diagnosed NHL cases worldwide. NHL is the most common hematologic malignancy and the tenth most common cancer worldwide, with nearly 386,000 new cases diagnosed in 2012.

About Copanlisib (Aliqopa)
Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells. The PI3K pathway is involved in cell growth, survival and metabolism, and its dysregulation plays an important role in follicular lymphoma. Copanlisib is administered as a 1-hour intravenous infusion on days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule. Treatment should be continued until disease progression or unacceptable toxicity.

The broad clinical development program for copanlisib also includes ongoing Phase III studies in indolent NHL (iNHL) patients who have relapsed or are refractory to prior therapies. The CHRONOS-3 Phase III study is evaluating copanlisib in combination with rituximab in relapsed iNHL and the CHRONOS-4 Phase III study is evaluating copanlisib in combination with standard immunochemotherapy in relapsed iNHL. More information about these trials can be found at www.clinicaltrials.gov.

Copanlisib is currently not approved by the European Medicines Agency (EMA) or other authorities outside of the U.S.

FDA Approves Amgen And Allergan’s MVASIâ„¢ (bevacizumab-awwb) For The Treatment Of Five Types Of Cancer

On September 14, 2017 Amgen (NASDAQ: AMGN) and Allergan plc. (NYSE: AGN) reported that the U.S. Food and Drug Administration (FDA) has approved MVASI (bevacizumab-awwb) for all eligible indications of the reference product, Avastin (bevacizumab) (Press release, Amgen, SEP 14, 2017, View Source [SID1234520515]). MVASI is the first anti-cancer biosimilar, as well as the first bevacizumab biosimilar, approved by the FDA. MVASI is approved for the treatment of five types of cancer, including in combination with chemotherapy for non-squamous non-small cell lung cancer (NSCLC), in combination with chemotherapy for metastatic colorectal cancer (mCRC), glioblastoma, metastatic renal cell carcinoma in combination with interferon alfa and in combination with chemotherapy for persistent, recurrent, or metastatic carcinoma of the cervix.

"The approval of MVASI marks a significant milestone for healthcare practitioners and patients as the first anti-cancer biosimilar approved in the United States," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "With decades of experience in oncology and biologics, Amgen continues to expand its biosimilar and oncology portfolios, and MVASI has the potential to advance access to high-quality, targeted cancer therapy."

Amgen is committed to developing high-quality biosimilars with a robust analytic and clinical package. Approval is based on the totality of evidence which includes structure, function, toxicity, pharmacokinetics, pharmacodynamics, immunogenicity, clinical safety and efficacy.1 The approval of MVASI was based on a comprehensive data package that demonstrated MVASI and bevacizumab are highly similar, with no clinically meaningful differences in terms of the efficacy, safety and immunogenicity between the products. Clinical studies included results from a Phase 3 trial in patients with NSCLC.

"MVASI is the first product from our collaboration with Amgen to be approved by the FDA and underscores our joint commitment to bring cancer biosimilars to market to help patients," said David Nicholson, chief research and development officer at Allergan. "We are committed to developing safe and effective therapies in critical disease areas, and MVASI is leading the way for additional oncology biosimilars from Amgen and Allergan."

Amgen and Allergan’s bevacizumab biosimilar is also undergoing review by the European Medicines Agency, following a Marketing Authorization Application submitted in December 2016. The companies are collaborating on the development and commercialization of four oncology biosimilars. Amgen has a total of 10 biosimilars in its portfolio, two of which have been approved by the FDA including MVASI.

About MVASI (bevacizumab-awwb) in the U.S.

MVASI is a biosimilar to bevacizumab, a recombinant immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to vascular endothelial growth factor (VEGF) and inhibits the interaction of VEGF with its receptors, VEGF receptor-1 and VEGF receptor-2, thus inhibiting establishment of new blood vessels necessary for the maintenance and growth of solid tumors.

MVASI is indicated for the treatment of mCRC, with intravenous 5-fluorouracil–based chemotherapy for first- or second-line treatment.

MVASI is indicated for the treatment of mCRC, with fluoropyrimidine- irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line bevacizumab-containing regimen.
MVASI is not indicated for adjuvant treatment of colon cancer.

MVASI is indicated for the treatment of NSCLC, with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent or metastatic disease.

MVASI is indicated for the treatment of glioblastoma, as a single agent for adult patients with progressive disease following prior therapy.
The effectiveness of bevacizumab products in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with bevacizumab products.

MVASI is indicated for the treatment of metastatic renal cell carcinoma with interferon alfa.

MVASI is indicated for the treatment of cervical cancer, in combination with paclitaxel and cisplatin or paclitaxel and topotecan in persistent, recurrent, or metastatic disease.

MVASI U.S. Important Safety Information

Boxed WARNINGS

Gastrointestinal (GI) Perforations

The incidence of gastrointestinal perforation, some fatal, in bevacizumab product-treated patients ranges from 0.3-3.2%. Fatal outcome was reported in <1% of bevacizumab-treated patients. Discontinue MVASI in patients with gastrointestinal perforation.

Surgery and Wound Healing Complications

The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in bevacizumab product-treated patients. Discontinue MVASI in patients with wound dehiscence. The appropriate interval between termination of bevacizumab products and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate MVASI for at least 28 days prior to elective surgery. Do not initiate MVASI for at least 28 days after surgery and until the surgical wound is fully healed.

Hemorrhage

Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous system hemorrhage, epistaxis, and vaginal bleeding occur up to 5-fold more frequently in patients receiving bevacizumab products. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving bevacizumab ranged from 0.4% to 6.9%. Do not administer MVASI to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue MVASI in patients with serious hemorrhage (ie, requiring medical intervention).

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the bevacizumab product-treated arm vs control included
GI fistulae (up to 2% in metastatic colorectal cancer)
Non-GI fistulae (<1% in trials across various indications; 1.8% in a cervical cancer trial)
Arterial thromboembolic events (grade ≥3, 2.6%)
Proteinuria (nephrotic syndrome, <1%)
Additional serious adverse events with increased incidence in the bevacizumab product-treated arm vs control included
GI-vaginal fistulae occurred in 8.3% of patients in a cervical cancer trial
Venous thromboembolism (grade 3-4, up to 10.6%) in patients with persistent, recurrent, or metastatic cervical cancer treated with chemotherapy and bevacizumab product
Hypertension (grade 3-4, 5%-18%)
Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
Infusion reactions with the first dose of bevacizumab product-treated patients were uncommon (<3%), and severe reactions occurred in 0.2% of patients
Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with MVASI
Pregnancy warning

Based on the mechanism of action and animal studies, bevacizumab products may cause fetal harm
Advise female patients that MVASI may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy
Advise females of reproductive potential to use effective contraception during treatment with MVASI and for 6 months after the last dose of MVASI
Advise nursing women that breastfeeding is not recommended during treatment with MVASI
MVASI may impair fertility
Most Common Adverse Events

Across indications, the most common adverse reactions observed in bevacizumab product-treated patients at a rate of >10% and at least twice the control arm rate were: epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis
Across all studies, bevacizumab product was discontinued in 8.4% to 21% of patients because of adverse reactions.
Please see full Prescribing Information, including Boxed WARNINGS, at www.Amgen.com.

Oncolytics Biotech® Announces First Patient Treated in MUK eleven Study

On September 14, 2017 Oncolytics Biotech Inc. (TSX: ONC) (OTCQX: ONCYF) (Oncolytics or the Company), a biotech company developing REOLYSIN (pelareorep), a first-in-class, systemically delivered immuno-oncolytic virus that activates the innate and adaptive immune systems, reported that the first patient has been treated in the Phase 1b trial MUK eleven, studying REOLYSIN in combination with Celgene Corporation’s immunomodulatory drugs (IMiDs), Revlimid or Imnovid as a rescue treatment in relapsing myeloma patients (Press release, Oncolytics Biotech, SEP 14, 2017, View Source [SID1234520513]).

"This is an important trial for Oncolytics as it’s the first to discretely examine the innate immunity component of REOLYSIN’s mechanism of action," said Dr. Matt Coffey, President and CEO of Oncolytics Biotech. "MUK eleven and REO 024, our trial evaluating the induction of an inflamed tumor phenotype of REOLYSIN in a combination with Keytruda, collectively demonstrate our strategy to assess the safety and efficacy of REOLYSIN in combination with immunomodulatory and immuno-oncology drugs, the impact of these combinations on the immune system and to explore new clinical applications."

"We are pleased to have enrolled the first patient in MUK eleven, a trial focused on a novel area of myeloma research," said Dr. Simon Ridley, Director of Research at Myeloma UK. "Our Clinical Trial Network is focused on strategic, collaborative and innovative approaches to delivering trials and treatments to patients and this pioneering trial has the potential to offer a novel future treatment strategy in myeloma."

MUK eleven is a first-of-its-kind immunotherapy trial that aims to modulate the immune system to target myeloma. The trial, run through the Myeloma UK Clinical Trial Network (CTN) in collaboration with charity Myeloma UK, the University of Leeds and Celgene, launched in March of this year and will recruit approximately 44 patients across up to eight CTN centres in the UK. MUK eleven will study REOLYSIN (pelareorep) in combination with Celgene’s Imnovid (pomalidomide) or Revlimid (lenalidomide) in patients whose myeloma is progressing while being treated with one of these IMiDs. In addition to assessing the safety and tolerability of these combinations, the trial will investigate whether the addition of REOLYSIN extends disease control in this patient group.

MUK eleven is a dose escalation trial where dose limiting toxicities (DLTs) will inform decisions to increase dose, and patients being treated with pomalidomide will be evaluated separately from those taking lenalidomide. Beginning at two CTN centres, cohorts of two participants each will be treated with REOLYSIN in combination with an IMiD. The first patient will receive one 28-day treatment cycle and if no DLTs are experienced at the end of the cycle, the second patient will begin treatment at the same dose. Doses may be escalated once participants in each cohort have completed the DLT monitoring period and will be increased between cohorts until the occurrence of DLTs define the maximum tolerated dose (MTD). Once the MTD has been identified with no associated safety issues, 10 additional patients will be enrolled at the MTD. Once a minimum of 12 patients in each IMiD group have been treated, up to six additional trial sites may be added to the trial. Based on this trial design, preliminary data are expected to be available in the first quarter of 2018.

About REOLYSIN
REOLYSIN is a non-pathogenic, proprietary isolate of the unmodified reovirus. A first-in-class systemically delivered immuno-oncolytic virus for the treatment of solid tumors and hematological malignancies. The compound induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses to treat a variety of cancers.

Atossa Genetics Announces Preliminary Results from Phase 1 Study of Topical Endoxifen

On September 14, 2017 Atossa Genetics Inc. (NASDAQ:ATOS), a clinical-stage pharmaceutical company developing novel therapeutics and delivery methods for breast cancer and other breast conditions, reported preliminary results from its Phase 1 dose escalation study of its proprietary topical Endoxifen (Press release, Atossa Genetics, SEP 14, 2017, View Source [SID1234520512]). All objectives were successfully met:

Safety: There were no clinically significant safety signals and no clinically significant adverse events in participants receiving topical Endoxifen.

Tolerability: Topical Endoxifen was well tolerated at each dose level and for the dosing duration utilized in the study.

Pharmacokinetics: Topical Endoxifen crossed the skin barrier when applied daily to the breast, as demonstrated by low but measurable Endoxifen blood levels detected in a dose-dependent fashion.
These data demonstrate the suitability of topical endoxifen for further clinical development.

Atossa expects to announce results from the oral arm of the Phase 1 study in the next 30-60 days.

The Phase 1 Study

The Phase 1 study was a double-blind, placebo-controlled, repeat dose study of 48 healthy female subjects. Atossa assessed safety, tolerability and the pharmacokinetics of proprietary formulations of both topical and oral Endoxifen dosage forms in varying dose levels over 28 days. The study was conducted in two parts based on route of administration. Results from the oral arm of the study are expected in the next 30 to 60 days.

Atossa’s Proprietary Endoxifen

Endoxifen is an active metabolite of tamoxifen. Tamoxifen is an FDA-approved drug to prevent new breast cancer as well as recurrent breast cancer in breast cancer patients. Tamoxifen itself must be broken down by the liver into active compounds (metabolites), of which Endoxifen is the most active.

Topical Endoxifen. A condition called breast density (or, MBD), typically diagnosed by a mammogram, has been shown to be an independent breast cancer risk factor. To date, 30 states require that findings of MBD be directly communicated to the patient. We believe a topical form of Endoxifen could potentially reduce MBD. Although oral tamoxifen has been shown to reduce MBD, the benefit-cost ratio is not acceptable to most physicians and their patients. For example, it is estimated that only ~ 2% of women at high-risk of developing breast cancer including those with MBD take oral tamoxifen to prevent breast cancer because of the risk of, or actual side-effects of, oral tamoxifen. Therefore we expect our next study to focus on the potential for Atossa’s topical Endoxifen to reduce MBD.

Oral Endoxifen. Although approximately one million breast cancer survivors take tamoxifen annually, up to half of them do not benefit from tamoxifen, meaning they are "refractory," for a number of reasons including that they do not properly metabolize tamoxifen. Low endoxifen levels in breast cancer patients taking oral tamoxifen are associated with an increased risk of recurrence or the development of new breast tumors. Thus providing oral Endoxifen directly to the patient without having to be metabolized may help to address this problem.

Based on the number of women at high-risk of developing breast cancer and the number of patients who have survived breast cancer but are not benefiting from tamoxifen, Atossa estimates that the potential markets for its proprietary oral and topical formulations of Endoxifen could each potentially exceed $1 billion in annual sales.

Next Steps

"Based on these positive preliminary results, we are advancing our topical Endoxifen into Phase 2 studies," commented Dr. Steven C. Quay, CEO and President. "We look forward to announcing the results from the oral arm of our Phase 1 study in the coming 30 to 60 days," continued Dr. Quay.

Breast Cancer Statistics

The American Cancer Society (ACS) estimates that approximately 250,000 women will be diagnosed with breast cancer in the United States this year and that approximately 40,000 will die from the disease. It is the second leading cause of cancer death in American women. Although about 100 times less common than women, breast cancer also affects men. The ACS estimates that the lifetime risk of men getting breast cancer is about 1 in 1,000; 2,470 new cases of invasive breast cancer will be diagnosed; and 460 men will die from breast cancer in 2017.

Positive Top-Line Results from Phase 3 PROSPER Trial of XTANDI (enzalutamide) in Patients with Non-Metastatic Castration-Resistant Prostate Cancer (pdf 324KB)

On September 14, 2017 Pfizer Inc. (NYSE: PFE) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Yoshihiko Hatanaka, "Astellas") reported that the Phase 3 PROSPER trial evaluating XTANDI (enzalutamide) plus androgen deprivation therapy (ADT) versus ADT alone in patients with non-metastatic (M0) CastrationResistant Prostate Cancer (CRPC) met its primary endpoint of improved metastasis-free survival (MFS) (Press release, Astellas, SEP 14, 2017, View Source [SID1234520511]). The preliminary safety analysis of the PROSPER trial appears consistent with the safety profile of XTANDI in previous clinical trials.

"Many prostate cancer patients who initiate androgen deprivation therapy will experience disease progression illustrated by a rising PSA level, and currently, there are no FDAapproved treatment options for patients with non-metastatic CRPC until they develop confirmed radiographic metastatic disease," said Neal Shore, M.D., director, CPI, Carolina Urologic Research Center.

Based on the results of PROSPER, the companies intend to discuss the data with global health authorities to potentially support expanding the label for XTANDI to cover all patients with CRPC.
"We are delighted with the significant results seen in the PROSPER study, showing that XTANDI plus ADT delayed clinically detectable metastases compared to ADT alone in patients with non-metastatic CRPC whose only sign of underlying disease was a rapidly rising prostate-specific antigen (PSA) level. We look forward to discussing the data with regulatory authorities," said Mace Rothenberg, M.D., chief development officer, Oncology, Pfizer Global Product Development. "XTANDI is already established as a standard of care for men with metastatic CRPC based on the results of prior studies, such as AFFIRM and PREVAIL, which
2 demonstrated that XTANDI delayed disease progression and improved overall survival in men with clinically detectable metastatic disease."

"We want to thank the patients, family members and clinicians who participated in the PROSPER trial and helped advance the scientific understanding of the potential role for XTANDI in this prevalent disease," said Steven Benner, M.D., senior vice president and global therapeutic area head, oncology development, Astellas. "We look forward to further analyzing the detailed efficacy and safety results from PROSPER, and submitting them for presentation at an upcoming major medical meeting."

As part of Pfizer and Astellas’ ongoing commitment to the clinical development of enzalutamide in areas of greatest unmet need, the companies initiated the PROSPER trial to evaluate the potential benefits of XTANDI in men with non-metastatic CRPC, an earlier stage of prostate cancer where there are currently no FDA-approved treatment options. On June 9, 2017, the companies announced an amendment to the PROSPER protocol, which accelerated the clinical trial completion date by two years.

XTANDI is currently approved for the treatment of metastatic CRPC based on clinical data from previous studies that showed a statistically significant overall survival benefit for XTANDI versus placebo in the metastatic CRPC setting. XTANDI has been prescribed to more than 185,000 patients globally since its first approval in 2012.

About PROSPER
The Phase 3 randomized, double-blind, placebo-controlled, multi-national trial enrolled approximately 1,400 patients with non-metastatic castration-resistant prostate cancer (CRPC) at sites in the United States, Canada, Europe, South America and the Asia Pacific region. PROSPER enrolled patients with prostate cancer that had progressed, based on a rising prostate-specific antigen (PSA) level despite androgen deprivation therapy (ADT), but who had no symptoms with no prior or present evidence of metastatic disease. The primary objective of the trial was metastasis-free survival (MFS). MFS is a measure of the amount of time that passes until a cancer can be radiographically detected as having metastasized, or spread, to other parts of the body. The trial evaluated enzalutamide at a dose of 160 mg taken orally once daily plus ADT, versus placebo plus ADT. For more information on the PROSPER trial go to www.clinicaltrials.gov.

XTANDI has not yet been evaluated by the FDA for the treatment of patients with nonmetastatic CRPC.

About Non-Metastatic Castration-Resistant Prostate Cancer
According to the American Cancer Society, more than 161,000 men are estimated to be diagnosed with prostate cancer in 2017.[i] Castration-resistant prostate cancer (CRPC) refers to the subset of men whose prostate cancer progresses despite androgen deprivation therapy.[ii] Non-metastatic CRPC means there is no clinically detectable evidence of the cancer spreading to other parts of the body (metastases), and there is a rising prostatespecific antigen (PSA) level. [iii] Many men with non-metastatic CRPC will go on to develop metastatic CRPC.[iv]

About XTANDI (enzalutamide) capsules
XTANDI (enzalutamide) is an androgen receptor inhibitor that blocks multiple steps in the androgen receptor signaling pathway within the tumor cell. In preclinical studies, enzalutamide
3 has been shown to competitively inhibit androgen binding to androgen receptors, and inhibit androgen receptor nuclear translocation and interaction with DNA. The clinical significance of this mechanism of action (MOA) is unknown.

XTANDI is approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). Additional ongoing studies, such as the ARCHES trial in metastatic hormone-sensitive prostate cancer and the EMBARK trial in non-metastatic hormone-sensitive prostate cancer, are continuing to evaluate the potential of enzalutamide to help patients in need.

Important Safety Information

Contraindications
XTANDI is not indicated for women. XTANDI can cause fetal harm and potential loss of pregnancy.

Warnings and Precautions
Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors, seizures were reported in 2.2% of patients. See section 5.1 of the Prescribing Information for the list of predisposing factors. It is unknown whether antiepileptic medications will prevent seizures with XTANDI. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Adverse Reactions
The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI patients from the two placebo-controlled clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. In the bicalutamide-controlled study of chemotherapy-naïve patients, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, upper respiratory tract infection, diarrhea, and weight loss.

In the placebo-controlled study of patients taking XTANDI who previously received docetaxel, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients.

In the placebo-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups. In the bicalutamide-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 38.8% of XTANDI patients and 37.6% 4 of bicalutamide patients. Discontinuations due to adverse events were reported for 7.6% of XTANDI patients and 6.3% of bicalutamide patients.

Lab Abnormalities: In the two placebo-controlled trials, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).

Infections: In the study of patients taking XTANDI who previously received docetaxel, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In the study of chemotherapy-naïve patients, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls (including fall-related injuries) occurred in 9% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms.
Hypertension led to study discontinuation in < 1% of patients in each arm.

Drug Interactions
Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI.

Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI.

If coadministration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see Full Prescribing Information for additional safety information.