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PSA Drop Seen with New Prostate Cancer Drug

  • - Urology / Nephrology News
  • Apr 02, 2012
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  • Viewed: 4936
  
Tags: | androgen deprivation therapy | androgen-independent prostate cancer | castration-resistant prostate cancer | crpc |

Half of a group of men with castration-resistant prostate cancer (CRPC) had biochemical responses to treatment with an investigational androgen receptor modulator, data from a preliminary clinical study showed.

During 12 weeks of treatment with galeterone, prostate-specific antigen (PSA) declined by at least 30% in 24 of 49 patients, 11 of whom had declines of 50% or more.

The single agent was generally well tolerated, with only one serious adverse effect was attributed to galeterone, R. Bruce Montgomery, MD, reported here at the American Association for Cancer Research (AACR) meeting.

“There was evidence of on-target effects by suppressing PSA in an androgen-regulated tumor,” said Montgomery, of the University of Washington in Seattle, during an AACR press briefing. There have been at least three radiographic responses, and we continue to that information.”

Galeterone is a semisynthetic steroid analog that targets three aspects of prostate cancer cell proliferation and survival. The drug inhibits CYP17 lyase, a key enzyme in the steroidogenic pathway involved in androgen production. The recently approved drug abiraterone (Zytiga) also targets CYP17 lyase.

Galeterone also inhibits androgen-receptor binding, the principal mechanism of action for bicalutamide and the investigational agent MDV3100.

Unlike other drugs approved for CRPC or in clinical development, galeterone disrupts prostate cancer cells’ internal androgen-receptor production.

The euphemistic term castration-resistant prostate cancer (CRPC) has slowly entered the everyday lexicon of those who study and treat prostate cancer. Ahmann and Crawford utilized this term in 1987. Emanating from what used to be called hormone-refractory prostate cancer and/or androgen-independent prostate cancer, this CRPC consensus definition was first formally reintroduced at a 2005 ODAC discussion on prostate cancer trial end points. Subsequently, in 2008, it was specifically defined in a Prostate Cancer Working Group Guidelines report, published in Journal of Clinical Oncology.

At that time, Scher et al recognized that despite medical or surgical castration, prostate cancers were still sensitive to subcastrate levels of androgens, either emanating from the adrenal cortex or from prostate cancer cells themselves (with direct intracrine activation of the androgen receptor cascade).

However, there have been some concerns expressed by clinicians, and more importantly by patients themselves, that the term castration implies some sort of testicular removal, which has a negative connotation for many men who have this disease.

Hormone-refractory prostate cancer and androgen-independent prostate cancer did not have this perceived stigma, but in contrast, they have proven to be considerably inaccurate, as second-generation androgen deprivation therapy clinical trials are beginning to demonstrate.

Therefore, we would like to propose that a term such as endocrine-resistant prostate cancer may be a better description to utilize with our colleagues and patients. It is both accurate and less emotionally charged. Seen in this fashion, it gives us in the field, as well as our patients, a clearer way to view therapeutic options (which will increase significantly in the years to come).

Therapeutically, if patients knew their disease was either endocrine sensitive or endocrine resistant, potentially approvable agents like Abiraterone, MDV-3100, and even estrogenic compounds could be clearly delineated from the evolving nonhormonal options that are also coming down the pike, like immunotherapy, targeted agents, and newer chemotherapies.

Montgomery reported findings from a phase I dose-finding study involving men with disease progression during androgen ablation therapy, but no prior chemotherapy. Participants were randomized to eight dose-escalation cohorts that received single or split daily doses ranging from 650 to 2,600 mg/d.

After 12 weeks of treatment, patients could enter an extension phase if they met certain eligibility criteria. The primary objective was to evaluate galeterone’s safety, but a preliminary efficacy assessment also was performed.

Chemotherapy in castrate-resistant prostate cancer
For men with metastatic prostate cancer, hormonal therapy usually provides disease control for a substantial period of time. However, the vast majority eventually develop progressive disease that is resistant to further hormone manipulation.

Until recently, cytotoxic chemotherapy was considered to be relatively ineffective in men with castrate-resistant prostate cancer. In early trials, objective response rates were 10 to 20 percent, and median survival generally did not exceed 12 months. However, regimens that include docetaxel have been associated with higher rates of both objective tumor regression and biochemical (prostate specific antigen [PSA]) response, as well as longer survival durations.

The use of cytotoxic chemotherapy for the treatment of castrate-resistant prostate cancer will be reviewed here, with a focus on taxanes, mitoxantrone, and estramustine, as well as new chemotherapy agents under development. An overview of other aspects of the management of advanced prostate cancer is presented separately.

Grade 1 and 2 adverse events occurred in 58% and 30%, respectively, of the study population. The most common adverse events were:

  Fatigue: 36.7%
  Abnormal liver function tests: 32.7% for aspartate transaminase (AST) and 30.6% for alanine transaminase (ALT)
  Nausea: 28.6%
  Diarrhea: 26.5%
  Pruritis 24.5%

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