On September 26, 2015 Medivation, Inc. (NASDAQ: MDVN) reported updated data from a Phase 2 trial evaluating the investigational use of enzalutamide as a single agent for the treatment of advanced triple-negative breast cancer (TNBC) (Press release, Medivation, SEP 26, 2015, View Source [SID:1234507573]). Results from an exploratory overall survival analysis of study data were presented during an oral plenary session at the 2015 European Cancer Congress in Vienna, Austria. The presentation was selected to be featured in the upcoming "Highlights Session" of the 2015 European Cancer Congress.
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"We are excited by these updated data as we continue to monitor patients in the trial. Findings from the provisional analysis demonstrate the potential for a diagnostic test to help select women with this particularly aggressive type of breast cancer who may benefit from enzalutamide treatment," said Javier Cortés, M.D., director of the breast cancer program at Vall D’Hebron Institute of Oncology and head of the breast cancer program at Ramon y Cajal University Hospital in Madrid. "This finding is promising and potentially important for patients with TNBC."
A novel gene expression profiling assay was developed using data derived from the Phase 2 trial in patients with advanced TNBC, with a goal of developing a diagnostic test that could select patients who may respond to enzalutamide treatment. Nearly half of the enrolled patients (47%) tested positive for the novel gene expression profiling assay. An exploratory analysis of updated overall survival data demonstrated that those TNBC patients on enzalutamide whose tumors tested positive for the gene expression profile ("diagnostic positive") have to date experienced a 10.5-month longer median survival duration compared to those patients on enzalutamide whose tumor tested negative for the gene expression profile ("diagnostic negative"). The exploratory analysis demonstrated that median overall survival to date for diagnostic positive advanced TNBC patients treated with enzalutamide was 18.0 months (95% CI: 12.0-21.3) compared with 7.5 months for diagnostic negative advanced TNBC patients treated with enzalutamide (95% CI: 4.8 – 11.2).
Medivation released its initial exploratory analysis of then current overall survival data at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in June 2015. At that time, the median overall survival in patients whose TNBC was diagnostic positive was not yet reached (95% CI: 12.9 months – not yet reached) and for those with diagnostic negative TNBC the median overall survival was 7.5 months (95% CI: 4.8 – 11.2). Medivation provided full details of the trial design in its Form 10-Q filed with the Securities and Exchange Commission on August 6, 2015.
The most common (reported in ≥ 10% of patients) adverse events reported as related to enzalutamide treatment in the intent-to-treat population were fatigue (35%), nausea (26%), decreased appetite (13%), diarrhea (10%), and hot flush (10%).
"The data presented today highlight the potential advantages of using a novel genomic profiling assay to identify patients who might respond to treatments," said Amy Peterson, M.D., vice president of clinical development at Medivation. "This approach could have implications for future development of targeted therapies in triple negative breast cancer."
About the Phase 2 Study
The Phase 2 open label single arm, multicenter trial enrolled 118 women with advanced TNBC that expressed any amount of androgen receptor by immunohistochemistry. The objective of the study was to evaluate the benefit of enzalutamide, 160 mg/day orally, as single agent therapy for advanced TNBC and to identify an appropriate biomarker to help select those women more likely to respond to therapy. The primary endpoint of the trial was the clinical benefit rate at 16 weeks (CBR16), defined as the proportion of women with a complete response (CR), partial response (PR), or stable disease for at least 16 weeks. Secondary endpoints of the trial included clinical benefit rate at 24 weeks (CBR24), and progression-free survival (PFS), defined as time from the date of first dose of study drug until documented disease progression or death due to any cause.
XTANDI is not approved for the treatment of advanced AR positive, TNBC. The diagnostic referred to in this press release is neither approved nor commercially available.
About XTANDI (enzalutamide) capsules
XTANDI is approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).
Enzalutamide Mechanism of Action
Enzalutamide is an androgen receptor inhibitor that acts on three different steps in the androgen receptor signaling pathway.
XTANDI (enzalutamide) capsules HCP Important Safety Information
Important Safety Information
Contraindications XTANDI is not indicated for women and is contraindicated in women who are or may become pregnant. XTANDI can cause fetal harm when administered to a pregnant woman.
Warnings and Precautions
Seizure In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of XTANDI patients and 0% of placebo patients. In Study 2, conducted in patients with chemotherapy-naive metastatic CRPC, seizure occurred in 0.1% of XTANDI patients and 0.1% of placebo patients. There is no clinical trial experience readministering XTANDI to patients who experienced a seizure, and limited safety data are available in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold; Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. 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%) reported from two combined clinical studies that occurred more commonly ( ≥ 2% over placebo) in XTANDI patients 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 Study 1, 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 Study 2, 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.
Lab Abnormalities: 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 Study 1, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In Study 2, 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. 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. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of all patients.
Drug Interactions
Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration cannot be avoided, reduce the dose of XTANDI.
Avoid strong or moderate CYP3A4 or CYP2C8 inducers as they can alter the plasma exposure to 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.