Novel treatment strategies

Biological background The androgen synthesis pathway is one part of the general steroidal biosynthesis pathways, and, as such, it is intimately related to the synthesis of glycocorticoids and mineralocorticoids. This close relationship to these related pathways can be problematic for every manipulation of steroid biosynthesis.

Therefore, a selective inhibition of enzymes that affect only part of the androgen synthesis pathway could be useful. Two enzymes have to been shown to be major candidates: the cytochrome p450c17 (CYP17) and the C17,20-lyase. CYP 17 catalyzes key reactions in the androgen synthesis pathway. Inhibition of one of these enzymes offers advantages of being relatively androgen selective and of blocking its synthesis wherever it occurs in the body (i.e., testes, adrenal glands or PCa cells).26

Inhibition of these biochemical steps is not accompanied by inhibition of mineralocorticoid synthesis, one of the limiting factors for a therapy with nonspecific cytochrome inhibitors such as ketokonazole. The CYP17 deficiency, a congenital disorder characterized by adrenal hyperplasia, defective synthesis of cortisol, and missing synthesis of sexual hormones, provides theoretical evidence for some anticipated side effects of a CYP17 inhibition.27


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Diminished cortisol production provokes a compensatory increase in pituitary adrenocorticotropic hormone (ACTH) release, with maintenance or increased production of mineralocorticoids. The ACTH release and consecutive mineralocorticoid excess can be effectively managed by low-dose glucocorticoids.

Selective targeting of androgen biosynthesis Abiraterone acetate is a orally administrated small molecule that potently, selectively, and irreversibly inhibits CYP 17.26 In several phase 2 trials, abiratereone produced, both as monotherapy and in combination with low-dose prednisone, effective therapeutic response with minimal side effects after docetaxel-based chemotherapy.28, 29 One study found a decrease in PSA of 50% or greater in 51% of patients with a median time to progression (TTP) of 169 days. Furthermore, a partial clinical response was seen (by RECIST criteria) in 8 of 30 patients (27%).28

Another study showed a 50% or greater PSA decline in 41% patients. This study showed that patients who were ketoconazole pretreated remained sensitive to abiraterone, albeit at a lower rate than patients who were not ketoconazole pretreated. The median TTP was 99 days in those patients with ketoconazole pretreatment and 198 days in the ketoconazole-naïve group.29

As anticipated, the most common adverse effects of abiraterone were related to excesses of mineralocorticoids and included mild hypokalemia, hypertension, and fluid retention.6 These adverse effects could be effectively managed by administration of the selective mineralocorticoid receptor anatagonist eplerone or low-dose corticosteroids.28, 29

The encouraging results of the phase 2 studies led to a multicenter phase 3 study in which 1,195 patients with docetaxel refractory CRPC were randomized. The treatment groups included abiraterone, abiraterone in combination with low-dose prednisone, and one group with prednisone alone in combination with placebo. In August 2010, following a protocol specified interim analysis, an independent data monitoring committee recommended that the study be unblended, as treatment with abiraterone had resulted in a significant improvement in overall survival from 10.4 to 14.8 months, which translated into a 36% decreased mortality risk.

This has led to widespread anticipation that abiraterone will soon receive FDA approval for treating chemorefractory, metastatic CRPC, joining docetaxel and sipuleucel-T (Provenge) as agents approved for CRPC, and cabazitaxel, which was recently approved for use in the specific post-chemotherapy CRPC clinical setting.26

TAK-700 and TOK-001 are two additional, relatively late-stage developments, selective inhibitors of the C17, 21-lyase. Both drugs are currently under investigation in phase 2 trials. TAK-700 has shown good tolerability in phase 1 trials, with common adverse events (AEs) being fatigue (62%), nausea (38%), constipation (35%), anorexia (35%), and vomiting (30%).

Doses above 300 mg twice daily produced a decrease in PSA of 50% or greater in 11 of 14 patients (70%). This trial is currently being continued with a daily administration of 400 mg TAK-700 twice daily in CRPC patients. A further phase 2 study of TAK-700 in men with increasing PSA (locally advanced patients) is also ongoing. The phase 1/2 trial of TOK-001 in CRPC was initiated in late 2009.6, 26

A new generation of AR antagonists

While the older generation of AR antagonists demonstrated activity after failure of primary gonadal suppression, their treatment efficacy was limited because of their partial AR agonist activity. MDV3100 is a new-generation antiandrogen that binds to the AR with a higher affinity than bicalutamide, reduces AR nuclear translocation, and impairs both DNA binding to androgen response elements and the recruitments of their coactivators.30

A phase 1/2 trial demonstrated remarkable success with a relatively low incidence of AEs. The overall TTP was 224 days, with a median of 147 and 287 days in patients with and without chemotherapy, respectively. The most common grade 3/4 AEs were fatigue (11%), asthenia (2%), and seizures (2%)s. Grade 3/4 AEs were observed at doses above 360 mg, and were generally resolved after dosage reduction.31 MDV3100 is in phase 3 studies in both pre- and post-chemotherapy CRPC patients.

Summary

Following the same trend in other cancer-treatment regimens to become more selective and target-specific, CRPC therapy will also change in coming years from mainly nonspecific, empiric treatments to highly potent and selective treatments. The new CYP 17 inhibitors abiraterone, TAK-700, and TOK-001 are effective inhibitors of the testosterone synthesis pathway, and MDV3100 is a highly potent inhibitor of the AR.

With these drugs, two major components of CRPC progression, ligand and receptor, are blocked. However, it must be acknowledged that even these new therapies are not curative, that treatment resistance does develop, and that the mechanisms associated with cancer progression despite treatment with these drugs are still poorly understood.

In conclusion, these new therapies are a milestone in the treatment of CRCP, but fail to reach the ultimate goal—its cure.

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