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Abiraterone Acetate geeft door CYP17 blokkade uitstekende resultaten bij prostaatkanker (70 tot 80% regressie in een gerandomiseerde fase III studie en bevestigt hormoongerelateerdheid van prostaatkanker. Artikel update 3 februari 2012

3 februari 2012: Inmiddels is Abiraterone door de FDA goedgekeurd en een vergelijkend middel MDV3100 zal snel volgen na recent gepubliceerde uitstekende studie resultaten. Klik hier voor meer informatie over Abiraterone en MDV3100 naast onderstaand artikel en artikel uit linkerkolom

27 februari 2011: Bron: Producent van Abetirone.

Inmiddels zijn de resultaten van een fase III studie vrijgegeven en lijkt Abiraterone snel een goedgekeurd medicijn te kunnen worden bij chemo resistente prostaatkanker. Hier een samenvatting van het studieverslag gehaald van de website van de producent:

Abiraterone Acetate Significantly Improved Overall Survival for Patients with Metastatic Advanced Prostate Cancer

Results observed in patients treated with abiraterone acetate plus prednisone/prednisolone whose disease progressed after docetaxel-based chemotherapy

Based on the results of this Phase 3 study, the Company plans to file marketing applications for abiraterone acetate with regulatory authorities worldwide

Note: Data in this release correspond to ESMO abstract LBA5

RARITAN, NJ, October 11, 2010 - Results from a pre-specified interim analysis of a randomized, placebo-controlled Phase 3 study, COU-AA-301, demonstrate that patients treated with the investigational agent abiraterone acetate plus low-dose prednisone/prednisolone showed a significant improvement in overall survival compared to patients treated with prednisone/prednisolone plus placebo. This study included 1,195 patients with metastatic advanced prostate cancer (also referred to as castration-resistant prostate cancer, or CRPC) previously treated with one or two chemotherapy regimens, at least one of which contained docetaxel.

The results of this randomized, placebo-controlled study were shared during a late-breaking presentation at the Presidential Symposium today at the 35th Annual European Society for Medical Oncology (ESMO) Congress.

Treatment with abiraterone acetate resulted in a 35 percent reduction in the risk of death (HR=0.65; 95 percent CI: 0.54, 0.77; p<0.0001) and a 36 percent increase in median survival (14.8 months vs. 10.9 months) compared with placebo.

Patients who received abiraterone acetate and low-dose prednisone/prednisolone also showed significant improvements in secondary study endpoints when compared to the prednisone/prednisolone plus placebo group: time to PSA progression (TTPP) [median 10.2 months for abiraterone acetate vs. 6.6 months for placebo, HR=0.58 (95 percent CI: 0.46, 0.73); p<0.0001] and an increase in radiographic progression-free survival (rPFS) [median 5.6 months for abiraterone acetate vs. 3.6 months for placebo, HR=0.67 (95 percent CI: 0.58, 0.78); p<0.0001]. Total PSA response, defined as greater than or equal to a 50 percent decrease from baseline, was achieved in 38 percent of patients treated with abiraterone acetate vs. 10 percent in the prednisone/prednisolone plus placebo group [p<0.0001].

Patients in the abiraterone acetate group experienced more mineralocorticoid-related adverse events than those in the prednisone/prednisolone plus placebo group. The most frequent adverse events were fluid retention (30.5 percent vs. 22.3 percent) and hypokalemia (17.1 percent vs. 8.4 percent). Grade 3/4 hypokalemia and hypertension were more frequent in the abiraterone acetate arm than in the placebo arm (3.8 percent vs. 0.8 percent and 1.3 percent vs. 0.3 percent, respectively). Liver function test abnormalities were observed in 10.4 percent of abiraterone acetate treated patients compared to 8.1 percent in the prednisone/prednisolone plus placebo group. Cardiac disorders were observed in 12.5 percent of abiraterone acetate patients vs. 9.4 percent of patients who received placebo. Mechanism-based adverse events were amenable to medical management and distinct from adverse events commonly associated with cytotoxic chemotherapy.

"Abiraterone acetate has the potential to meet a significant unmet need, so this news will be incredibly important to prostate cancer patients and their families," said Johann S. de Bono, MD, FRCP, MSc, PhD, The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, one of the lead COU-AA-301 investigators. "We are very pleased with the definitive results of this rigorous study, which show that abiraterone acetate may extend survival for men with metastatic advanced prostate cancer that progressed after treatment with docetaxel."

The Company plans to file marketing applications for abiraterone acetate with regulatory authorities in the U.S. and Europe by the end of the year. Applications in the rest of the world will follow, according to local regulatory requirements. If approved, abiraterone acetate will be commercialized and distributed by Centocor Ortho Biotech Inc. in the U.S. and by Janssen Pharmaceutical Companies in all other countries around the world.

"Globally, prostate cancer, the fifth most common cancer overall, is a significant public health problem," said Howard I. Scher, MD, Memorial Sloan-Kettering Cancer Center, one of the lead COU-AA-301 investigators. "These results are important because men with progressive metastatic, castration-resistant prostate cancer often have a poor prognosis and currently have few treatment options."

A program that provides early access to abiraterone acetate for eligible patients is expected to be opened in the U.S. in October and will be opened in sites outside the U.S. in the following months, with the timing of the program contingent on local health authority and ethics committee approvals.

"The results of this abiraterone acetate Phase 3 study in patients with metastatic advanced prostate cancer bring us closer to achieving our goal of developing extraordinary preventive, diagnostic and therapeutic solutions based on our tumor microenvironment strategy," said William N. Hait, MD, PhD, Global Therapeutic Head, Oncology, Ortho Biotech Oncology Research & Development. "We believe that abiraterone acetate is an important medical advance, and we look forward to further developing oncology therapeutic options that may impact patients' lives."

Ortho Biotech Oncology Research & Development, a unit of Cougar Biotechnology, Inc., previously announced that the Independent Data Monitoring Committee recommended unblinding this Phase 3 study after a pre-specified interim analysis demonstrated a statistically significant improvement in median overall survival and an acceptable safety profile. The IDMC also recommended that patients in the prednisone/prednisolone plus placebo group be offered treatment with abiraterone acetate.

Study Design
This randomized, double-blind placebo-controlled Phase 3 study was conducted in 147 centers in 13 countries. Patients with metastatic advanced prostate cancer previously treated with docetaxel (N=1,195) were randomly assigned 2:1 to receive abiraterone acetate (1000 mg once daily) plus prednisone/prednisolone (5 mg twice daily) (N=797), or placebo plus prednisone/prednisolone (N=398). The primary endpoint was overall survival.

24 juni 2008: Bron: JCO Early Release, published online ahead of print Jul 21 2008
Journal of Clinical Oncology, 10.1200/JCO.2007.15.9749

Onderzoekers hebben in een fase I studie bij 21 prostaatkankerpatienten gevonden dat wanneer prostaatkankerpatienten dagelijks een pil nemen met abiraterone Acetate de PSA waarden teruglopen en de tumoren slonken met 70 tot 80 %. De onderzoekrs benadruikken dat hiermee wordt bewezen dat prostaatkanker in meerderheid door verstoring in de hormoonhuishouding  wordt veroorzaakt. O.i. is dat al 20 jaar bekend maar de reguliere oncologie wil er maar niet aan en bljift bestralen en opereren en chemo geven.  Wel uiteraard een hoopgevende studie omdat de tumoren echt afsterven. De vraag is nu worden mannen met prostaatkanker ook resistent tegen dit middel, maar dat zal de toekomst utiwijzen. Hier het abstract van de studie en daaronder een abstract van een studie waar wordt gekeken naar de blokkade van CYP17, ook met andere middelen.

Received December 28, 2007
Accepted May 14, 2008
 

Phase I Clinical Trial of a Selective Inhibitor of CYP17, Abiraterone Acetate, Confirms That Castration-Resistant Prostate Cancer Commonly Remains Hormone Driven

Gerhardt Attard, Alison H.M. Reid, Timothy A. Yap, Florence Raynaud, Mitch Dowsett, Sarah Settatree, Mary Barrett, Christopher Parker, Vanessa Martins, Elizabeth Folkerd, Jeremy Clark, Colin S. Cooper, Stan B. Kaye, David Dearnaley, Gloria Lee, and Johann S. de Bono^*

From the Royal Marsden NHS Foundation Trust, and The Institute of Cancer Research, Sutton, Surrey, United Kingdom; and Cougar Biotechnology, Los Angeles, CA.
 

^* To whom correspondence should be addressed. E-mail: johann.de-bono@icr.ac.uk

Purpose: Studies indicate that castration-resistant prostate cancer (CRPC) remains driven by ligand-dependent androgen receptor (AR) signaling. To evaluate this, a trial of abiraterone acetate—a potent, selective, small-molecule inhibitor of cytochrome P (CYP) 17, a key enzyme in androgen synthesis—was pursued.

Patients and Methods: Chemotherapy-naïve men (n = 21) who had prostate cancer that was resistant to multiple hormonal therapies were treated in this phase I study of once-daily, continuous abiraterone acetate, which escalated through five doses (250 to 2,000 mg) in three-patient cohorts.

Results: Abiraterone acetate was well tolerated. The anticipated toxicities attributable to a syndrome of secondary mineralocorticoid excess—namely hypertension, hypokalemia, and lower-limb edema—were successfully managed with a mineralocorticoid receptor antagonist. Antitumor activity was observed at all doses; however, because of a plateau in pharmacodynamic effect, 1,000 mg was selected for cohort expansion (n = 9). Abiraterone acetate administration was associated with increased levels of adrenocorticotropic hormone and steroids upstream of CYP17 and with suppression of serum testosterone, downstream androgenic steroids, and estradiol in all patients. Declines in prostate-specific antigen (PSA) 30%, 50%, and 90% were observed in 14 (66%), 12 (57%), and 6 (29%) patients, respectively, and lasted between 69 to 578 days. Radiologic regression, normalization of lactate dehydrogenase, and improved symptoms with a reduction in analgesic use were documented.

Conclusion: CYP17 blockade by abiraterone acetate is safe and has significant antitumor activity in CRPC. These data confirm that CRPC commonly remains dependent on ligand-activated AR signaling.

Hier nog een abstract van een studie naar CYP17 blokkades:

1: Curr Opin Pharmacol. 2008 Jul 8. [Epub ahead of print] Links