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Prostate cancer: abiraterone and enzalutamide are new treatments

Prostate cancer: abiraterone and enzalutamide are new treatments

Prostate cancer (PCa) was responsible for 1.1 million new cases and 300,000 deaths worldwide in 2012. In Brazil, the National Cancer Institute (INCA) estimates 70,000 new cases this year. The justification for the increase in incidence over the past three decades has been the discovery of PSA and its indiscriminate use as a screening test.

Prostate cancer treatment is multidisciplinary, with the urologist, oncologist, and radiotherapist working together at various times during the course of the disease. In a simplistic way, the treatment is divided into the treatment of localized disease and recurrent / metastatic disease.

Treatment of localized disease is not the focus of today. Being brief, it consists essentially of surgery (prostatectomy) or radiotherapy (with and without androgen deprivation), and the choice is based on the patient's clinical condition, tumor aggressiveness and side effects profile.

However, about 5-10% of patients will present with metastatic disease at diagnosis and a variable portion of patients initially treated as a localized disease will have a biochemical (PSA elevation) or clinical recurrence (appearance of distant metastases). The treatment of the disseminated disease is systemic and should preferably be conducted by an oncologist with experience in this type of tumor. These two new drugs have demonstrated efficacy in the context of advanced disease and, therefore, their goal is to keep prostate cancer under control. The role of androgens in stimulating the multiplication of benign or benign prostate cells was discovered by Charles Huggins in 1941 and based on this the first line of treatment was developed for

Suppression of testosterone levels can be achieved by surgical extraction of the testicles (bilateral orchiectomy) or by drugs that act by blocking the hypothalamic-pituitary-adrenal axis, pituitary gland and the secretion of gonadotrophic hormones (FSH and LH), such as goserelin, leuprolide or degarelix. Most patients achieve a reduction in lesions (clinical response) or a decrease in PSA at this stage known as castration-sensitive disease.

Unfortunately, almost all patients will develop with a new PSA elevation or increased number / of the metastases (clinical progression), and a new therapy should be instituted at this time (disease resistant to castration).

Initially, it was believed that this resistance to TDA was due to the acquisition of new mutations, which would alter the behavior of the tumor, which now would proliferate independent of the hormonal blockade. These patients began to be treated with chemotherapy - and docetaxel was the drug that showed the best results.

In studying patients with castration-resistant disease, the investigators came to two important conclusions: that tumor cells were partially dependent on androgens, and that even patients undergoing bilateral orchiectomy had circulating hormones from other sources (adrenal gland, for example).

It was in this context that the drug called abiraterone emerged and has been playing a prominent role in the treatment of metastatic prostate cancer resistant to castration. It acts through the selective and irreversible inhibition of the enzyme CYP17, responsible for the synthesis of androgens in the adrenal and in the tumor from the precursor pregnolone. The recommended dose is 1000 mg once daily (4 tablets of 250 mg), 1 hour before or 2 hours after the meal.

The selective inhibition of CYP17 impairs the production of glucocorticoids, reducing cortisol production and generating an increase in ACTH with a consequent increase in mineralocorticoid production. Therefore its main adverse effects are hypertension, hypokalemia and edema. Concurrent administration of corticosteroids is aimed at minimizing such adverse effects and discontinuation of treatment for toxicity is an uncommon event.

The pivotal study COU-AA-302, which led to drug approval in patients not previously exposed to chemotherapy, randomized 1,088 patients with castration-resistant metastatic prostate cancer to receive abiraterone 1000 mg / day with prednisone 10 mg / day or placebo with prednisone 10 mg / day. The most recent results were presented in September 2014 in Madrid and revealed that after four years of follow-up, the arm containing abiraterone significantly prolonged overall survival (OS) (34.7 versus 30.3 months). In addition, abiraterone was associated with reduced use of opioids to control pain, improved quality of life, and postponed the need for chemotherapy.

Parallel to the development of abiraterone, another agent that changed the paradigm in cancer treatment of advanced prostate has been developed: the enzyme. With a different mechanism of action, it binds to the androgen receptor inside the cell, inhibiting its translocation to the nucleus and binding to the DNA molecule. By doing so, it inhibits the synthesis of essential factors for cell multiplication. The recommended dose is 160 mg single daily dose (4 40 mg capsules) and does not require concomitant use of corticosteroids. The PREVAIL trial randomized 1,717 patients with castration-resistant metastatic CaP not exposed prior to chemotherapy who received either enzyme or placebo. The study was closed early because a pre-planned interim analysis already showed a benefit for the enzyme-linked arm (32.4 versus 30.2 months). In addition, the drug delayed the time to PSA elevation, time to the first bone complication due to the disease and, like abiraterone, postponed the initiation of chemotherapy.

An important study presented at the last American Congress demonstrated a significant gain in survival when chemotherapy is associated with TDA (initial castration) in those cases with large metastases and with visceral lesions at diagnosis. However, for the majority of patients with small volume of metastatic disease, the primary goal of treatment is to maintain quality of life with the lowest possible toxicity. To this end, these two drugs proved to be the best options.

These two new drugs have shown efficacy in the context of advanced disease, and thus their goal is to keep prostate cancer under control for as long as possible while maintaining quality of life. Even though they have been tested and proven efficacious in those patients who have already received docetaxel, the great niche of these agents appears to be prior to chemotherapy, often poorly tolerated in elderly and frail patients. Still, they are being tested in adjuvant treatment (shortly after surgery or radiotherapy) in order to increase the chance of cure of patients with localized disease, however use in this setting is still experimental and should not be used outside clinical research text .


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