FDA Pipeline: Advances in Prostate Cancer, Urothelial Cancer, Myelofibrosis, and More

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In the past few weeks, the U.S. Food and Drug Administration (FDA) has issued regulatory decisions in prostate cancer, urothelial cancer, myelofibrosis, breast cancer, pediatric brain cancer, leukemia, and skin cancer.

Breakthrough Therapy Designation for Niraparib in Metastatic Castration-Resistant Prostate Cancer

The FDA granted Breakthrough Therapy designation for niraparib, an orally administered poly (ADP-ribose) polymerase inhibitor, for the treatment of patients with BRCA1/2-mutated metastatic castration-resistant prostate cancer who have received prior taxane chemotherapy and androgen receptor–targeted therapy. BRCA1/2 mutations are the most common DNA repair gene defects in patients with metastatic castration-resistant prostate cancer, and patients with a BRCA1/2 mutation are at an elevated risk for both prostate cancer occurrence and more aggressive disease.

The Breakthrough Therapy designation is based on data from the GALAHAD study, a phase II, multicenter, open-label clinical trial evaluating the efficacy and safety of niraparib in the treatment of adult patients with metastatic castration-resistant prostate cancer and DNA repair gene defects who had received treatment with next-generation androgen receptor–targeting therapies and docetaxel. Data from GALAHAD were recently presented at the European Society for Medical Oncology (ESMO) 2019 Annual Congress as a late-breaking abstract.

Priority Review for Enfortumab Vedotin in Locally Advanced or Metastatic Urothelial Cancer

The FDA accepted a biologics license application for the investigational agent enfortumab vedotin and granted Priority Review to the agent for the treatment of patients with locally advanced or metastatic urothelial cancer who have received programmed cell death protein 1/ligand 1 inhibitor (PD-1/PD-L1) and who have received a platinum-containing chemotherapy in the neoadjuvant or adjuvant setting for locally advanced or metastatic disease. The filing is based on results from the first cohort of patients in the phase II EV-201 trial, which were presented at the 2019 ASCO Annual Meeting. Under the Prescription Drug User Fee Act, the FDA has set a target action date of March 15, 2020.

Enfortumab vedotin is a novel investigational antibody-drug conjugate that targets Nectin-4, a protein that is highly expressed in urothelial cancers. The FDA granted enfortumab vedotin Breakthrough Therapy designation in March 2018 for patients with locally advanced or metastatic urothelial cancer whose disease has progressed during or following checkpoint inhibitor therapy.

EV-201 is an ongoing, single-arm trial of enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/PD-L1 inhibitor, including those who have also been treated with a platinum-containing chemotherapy (cohort 1) and those who have not received a platinum-containing chemotherapy and who are ineligible for cisplatin (cohort 2). In cohort 1, 128 patients were enrolled at multiple centers internationally.

The primary endpoint of EV-201 is confirmed objective response rate per blinded independent central review. Secondary endpoints include assessments of duration of response, disease control rate, progression-free survival, overall survival, and safety and tolerability. The study continues to enroll patients in cohort 2.

Fast Track Designation for Imetelstat in Relapsed or Refractory Myelofibrosis

The FDA granted Fast Track designation to imetelstat—a novel, first-in-class telomerase inhibitor—for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis whose disease has relapsed after or is refractory to janus kinase (JAK) inhibitor treatment, or relapsed or refractory myelofibrosis. The Fast Track designation includes patients with primary myelofibrosis and myelofibrosis developed after essential thrombocythemia or polycythemia vera. There are currently no marketed drugs specifically approved for relapsed or refractory myelofibrosis, representing a significant unmet medical need.

The designation was based on data from IMbark, a phase II trial to evaluate two starting dose levels of imetelstat (either 4.7 mg/kg or 9.4 mg/kg administered by intravenous infusion every 3 weeks) in patients with intermediate-2 or high-risk myelofibrosis who have relapsed after or are refractory to prior treatment with a JAK inhibitor. The co-primary efficacy endpoints for the trial are spleen response rate and symptom response rate. Key secondary endpoints are safety and overall survival. IMbark is closed to new patient enrollment.

Labeling Supplement Approval for Neratinib in the Extended Adjuvant Treatment of HER2-Positive Early-Stage Breast Cancer

The FDA approved a labeling supplement for neratinib for the extended adjuvant treatment of HER2-positive early-stage breast cancer. With the approval of the labeling supplement, the label now includes safety information based on interim results from the phase II CONTROL trial, a study evaluating antidiarrheal prophylaxis or dose escalation in the reduction of neratinib-associated diarrhea.

The study has a primary endpoint of the incidence of grade 3 or higher diarrhea. Interim data from the trial showed that the addition of prophylactic treatment with loperamide plus budesonide reduced the discontinuation rate due to neratinib-associated diarrhea to 11% vs a discontinuation rate of 18% with loperamide alone.

In the ongoing CONTROL trial, patients with HER2-positive early-stage breast cancer who have completed trastuzumab-based adjuvant therapy receive neratinib daily for 1 year. The trial initially tested high-dose loperamide prophylaxis given for the first two cycles (56 days) of treatment (12 mg on days 1–14, 8 mg on days 15–56, and as needed thereafter). The CONTROL trial was then expanded to include four additional cohorts. One cohort received the combination of loperamide and budesonide. For the 64 patients who received the combination of loperamide plus budesonide, the incidence of grade 3 diarrhea was 28% compared to 32% for patients treated with loperamide alone. Diarrhea leading to treatment discontinuation declined to 11% in the loperamide plus budesonide cohort, compared to 18% in the loperamide alone cohort.

Neratinib was approved by FDA in July 2017 for the extended adjuvant treatment of adult patients with early-stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy.

Rare Pediatric Disease Designation for OT101 in Diffuse Intrinsic Pontine Glioma

The FDA granted Rare Pediatric Disease designation to OT101 (Trabedersen) for the treatment of diffuse intrinsic pontine glioma. The FDA grants Rare Pediatric Disease designation for diseases with serious or life-threatening manifestations that primarily affect people aged from birth to 18 years old, and that affect fewer than 200,000 people in the United States.

Brainstem tumors comprise approximately 10% to 15% of all pediatric brain tumors. Diffuse intrinsic pontine glioma is the most common brainstem tumor and the second most common malignant brain tumor of childhood.

OT101, a first-in-class RNA therapeutic, is designed to abrogate the immunosuppressive actions of TGF-beta 2. In a completed phase II trial, OT-101 exhibited clinically meaningful single-agent activity and induced durable complete and partial responses in recurrent and refractory adult high-grade glioma patients, including adults with glioblastoma multiforme. 

FDA Clearance for Xpert BCR-ABL Ultra Test

The FDA granted clearance to the Xpert BCR-ABL Ultra test for monitoring disease burden in patients with chronic myeloid leukemia (CML). Xpert BCR-ABL Ultra, an in vitro diagnostic test, is the first FDA-cleared test of its kind capable of delivering accurate molecular results from whole blood samples in under 3 hours.

One of the most important aspects of managing CML is regular and frequent monitoring of a patient's response to therapy by measuring BCR-ABL gene transcript levels as an indicator of treatment efficacy and as a predictor of relapse.

“Until now, tests for BCR-ABL have not been automated or designed to be run on-demand, which has limited the potential impact of a same-day result in the management of [patients with] CML. Because Xpert BCR-ABL Ultra is aligned to the International Scale on a lot-to-lot basis, accuracy and comparability of results is assured no matter which lab or even where in the world the test is performed.  In addition, the added sensitivity provides physicians with the information they need to confidently optimize individual treatment strategies for their patients with CML, including identifying patients who might be considered for a trial of therapy discontinuation,” commented the manufacturer of the test.

FDA Clearance for Temporary Radation Therapy Product CivaDerm

The FDA granted clearance to the temporary radiation therapy product CivaDerm, which has been designed for intraoperative or surface radiation to treat skin cancer and other lesions.

The polymer-encapsulated brachytherapy device can be applied like a bandage to provide a low–dose-rate brachytherapy treatment option for patients with skin cancer. CivaDerm is designed with gold shielding, enabling only one side of the radiation device to be active. A physician places the active side of the device on the targeted area. Patients wear the bandage over a 5-day window. CivaDerm will fully deliver the physician’s prescribed dose of radiation.

CivaDerm may allow health-care providers to offer radiation therapy for less cost without the need for purchasing expensive equipment. It may also enable patients to reduce the number of visits to a facility during treatment.


The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.