Zytiga was in news today, but more so were its competitors, Provenge and MDV3100. The big news was early unblinding of Zytiga trial in metastatic prostate cancer patients due to significant improvement seen in progression-free survival (PFS) and other endpoints.
The Independent Data Monitoring Committee (IDMC) unanimously recommended unblinding the study based on a planned interim analysis in which differences in radiographic progression-free survival, overall survival, and secondary endpoints were observed that constitute evidence of clinical benefit as well as continued evidence of favorable safety in patients receiving abiraterone acetate plus prednisone as compared to those receiving placebo plus prednisone. Based on these results, the IDMC also recommended that patients in the placebo arm be offered treatment with ZYTIGA.--Press Release, Janssen Research & Development, LLC
ABOUT PHASE 3 TRIAL
Company: Janssen Research & Development, LLC (part of Janssen Pharmaceutical Companies of Johnson & Johnson)
Drug: Zytiga (generic name: abiraterone acetate)
Approved indication: metastatic castration-resistant prostate-cancer (CRPC) patients previously treated with docetaxel based chemotherapy. Approved in April 2011 by the US FDA.
Current Phase 3 trial (COU-AA302): international, randomized, double-blind, placebo-controlled in patients not previously treated with chemotherapy.
n=1,000 patients randomized.
Treatment arm: Zytiga 1,000 mg per day plus prednisone 5 mg per day
Placebo arm: placebo plus prednisone 5 mg per day.
Primary endpoints: radiographic progression-free survival (PFS) and overall survival (OS)
Secondary endpoint: clinical benefit and continued evidence of favorable safety.
Interim analysis: IDMC saw significant improvement in radiographic PFS, OS, clinical benefit and safety profile in treatment arm that it recommended unblinding and placebo be crossovered to treatment arm.
J&J will present full data at upcoming cancer meeting, probably ASCO(?) and the company plans to file for FDA approval in 2012-2H.
WHAT DOES THIS ALL MEAN
The press release does not mention PFS or OS in months, yet today's news outlets had a great time predicting further slipping of Provenge market share and good news for OTHER drugs in development, such as Medivation's MDV3100, which these news articles say are “like” Zytiga, but that ain't true.
The likes of MDV3100 are not Zytiga clones; they inhibit androgen receptor (AR) function, but by a very different mechanism (see a previous post, here). The only thing common between the two is that they are small molecules targeting AR pathway, whereas Provenge is a cell-based vaccine.
While the journalists/writers of over 80 news articles have exercised their right to predict doom and gloom scenario for Dendreon's Provenge, which is already having difficulty establishing market share, they have overlooked a laundry list of toxicity problems with Zytiga.
Toxicity is one long-term wrench in this calculation.
Clinical trials, by nature, are carefully designed to exclude a “typical” patient, like my uncle, for whom prostate is one of the problem besides heart, blood pressure, diabetes, and so on. The future drug wars will center on which drug my uncle can use!
It may not be Zytiga. It may be MDV3100, or maybe some others on the horizon, including Aragon's ARN-509. (see long list here)
The Zytiga press release lists these safety concerns:
- Cardiovascular ... may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial.
- Hepatotoxicity. The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied... Drug Interactions - ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6.
- Adrenocortical Insufficiency (AI)
- Adverse Reactions - The most common adverse reactions (greater than or equal to 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.
- Contraindications - ZYTIGA® (abiraterone acetate) may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant.
- Trial Shows Benefit in Using Prostate Cancer Drug Early. By Andrew Pollack. New York Times. March 8, 2012
- Zytiga Did Not Extend Survival In Key Clinical Trial -- Yet. By Matthew Herper. Forbes. March 8, 2012.
- StudyUnblinded: ZYTIGA® (abiraterone acetate) Plus Prednisone forAsymptomatic or Mildly Symptomatic Chemotherapy-Naive Patients withMetastatic Castration-Resistant Prostate Cancer. Press Release, J&J. MarketWatch. March 8, 2012
- J&J unblind Zytiga phase 3 trial in pre-chemotherapy castrate-resistant prostate cancer. By Sally Church. Pharma Strategy Blog. March 8, 2012.
- J&JProstate Cancer Drug Scores Big Win, Hurts Dendreon, Helps Medivation. By Adam Feuerstein. The Street. March 8, 2012
- MDV1300Making a Mark While Provenge Takes a Deep Plunge. November 3, 2011.
- TheProstate Cancer: New drugs in the post “Abiraterone-Jevtana-Provenge”world. October 30, 2010.
- Andthe three co-winners in the 2010 race to beat Metastatic AdvancedProstate Cancer are Abiraterone, Jevtana and Provenge. October 14, 2010