Thursday, October 14, 2010

And the three co-winners in the 2010 race to beat Metastatic Advanced Prostate Cancer are Abiraterone, Jevtana and Provenge

Following the results of a randomized, placebo-controlled Phase 3 study COU-AA-301  released at the 35th Annual European Society for Medical Oncology (ESMO) Congress on October 11, 2010 (ESMO abstract LBA5), abiraterone has emerged as a third new treatment option for metastatic advanced prostate cancer (also referred to as hormone-refractory or castration-resistant prostate cancer [HRPC or CRPC]) this year. 
The other two drugs approved earlier this year are:  a chemotherapy agent Jevtana by Sanofi-Aventis and a cancer vaccine Provenge by Denderon.  All three drugs are first-in-class therapies.  Abiraterone, discovered by Mike Jarman at Institute of Cancer Research (ICR), UK,  inhibits CYP17A1 enzyme that acts as a gatekeeper converting Progestagens to Androgens (that includes testosterone and DHT).  Jevtana (cabazitaxel), a semi-synthetic taxane, is a microtubule inhibitor, and Provenge (sipuleucel T) is a novel cancer vaccine.

The COU-AA-301 Abiraterone Phase III trial included 1,195 patients with metastatic advanced prostate cancer previously treated with other options, including, docetaxel-based chemotherapy regimens.  The 797 patients randomly assigned to abiraterone acetate plus the prednisone (steroid) had a 3.9 month survival advantage over those treated with the steroid plus a placebo (n = 398).  This 3.9 month survival advantage was a factor in declaring the study “successful” and unblinding well before its completion.

Johnson & Johnson Press Release explains: “ 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. . . 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].”  The mineralocorticoid-related adverse events, such as, fluid retention and hypokalemia, were mechanism-based, and are easily managed in clinic.
The survival advantage of 3.9 months with abiraterone (similar to 2.4 months in Jevtana study or 4.1 months by Provenge) should be taken in context.  These were the sickest patients.  Once the drug enters mainstream, the advantage may turn out be much higher and will give the surgeons and urologists much more wiggle room to mix-and-match therapies.  Cost will always weigh in (!) a three-dose treatment schedule of Provenge regimen will set you back $93,000. 

Primer:  Prostate Cancer Options

Today, prostate cancer patients have an array of choices: wait-and-watch, local radiation (radioactive seed implant), robotic surgery, hormone and chemotherapy, and others (see NCI Prostate Treatment Options).  In early cancer, radiation and surgery may be enough; advanced cancer need hormone therapy and metastatic (often hormone-refractory) calls for aggressive treatment.  
Hormone therapy is designed to block production and release of androgens (using Gonadotropin-Releasing Hormone GnRH] agonists) or androgen receptor binding and signaling (using antiandrogens and androgen blockers.)  

*GnRH agonists include leuprolide (Lupron, Eligard, Viadur), goserelin (Zoladex), triptorelin (Trelstar) and histrelin (Vantas).   One serious side effect is that they can induce “flare,” a sudden increase of testosterone, early in treatment. 
*GnRH antagonist, such as degarelix (Firmagon) are new in the toolbox, they also reduce testosterone production but without inducing “flare." 

*Antiandrogens include bicalutamide (Casodex), flutamide (Eulexin), and nilutamide (Nilandron) are competitive inhibitors of 5-alpha dihydrotestosterone (DHT) for androgen receptor (AR) binding. These drugs typically are given along with an GnRH agonist or given before taking an Gn-RH agonist.  
*Androgen blockers, Aminoglutethimide (Cytadren) and ketoconazole (Nizoral) work by dampening testosterone and androgens production in adrenals and testicles. 
 These hormone interventions come with unpleasant side effects: bone (osteoporosis) and muscle loss, hot flashes, loss of libido, weight gain, and to complicate matters, GnRH agonists are under FDA safety review for possible cardiovascular and diabetes risk (FDA Drug Safety Communication: Ongoing Safety Review of GnRH Agonists and possible increased risk of diabetes and certain cardiovascular diseases05/23/2010).  If GnRH hormones are ever restricted, it will throw a monkey wrench in the prostate cancer management.  

In any case, most hormone-dependent cancers become refractory after one to three years despite aggressive hormone therapy.  Often the patients (about 20%) buy another  half-a-year to two by discontinuing the GnRH and antiandrogen cocktail; this slows tumors with mutant AR that have started using the hormone drugs themselves as growth factors.  Eventually, a combination of chemotherapy, Avastin, thalidomide and prednisolone are tried with mixed success.  Up until the arrival of the three new drugs (abiraterone, Jevtana and Provenge), the standard therapy, docetaxel, conferred a median survival of only two to three months.   

Abiraterone, Jevtana and Provenge may prove to be the three knights taking a bold charge. 

Abiraterone developed by Janssen Pharmaceutical Companies of Johnson & Johnson group
Jevtana developed by Sanofi-Aventis SA
Provenge a cancer vaccine developed by Dendreon Inc.
Lupron, Abbott Laboratorie
Eligard, Sanofi-Aventis
Synarel, Pfizer
Trelstar, Watson Pharmaceutical
Vantas, Endo Pharmaceuticals
Viadur, Bayer
Zoladex, AstraZeneca

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