Dutasteride In The Treatment Of Hormone Refractory Prostate Cancer

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 26 Sep 2008 - 4:00 PDT

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UroToday.com - Incidence of prostate cancer is on the rise. Approximately 10 to 20 percent of men with prostate cancer present with metastatic disease, and in many others metastases develop despite treatment with surgery or radiotherapy. Progression to androgen-independent prostate cancer takes 5-7 years and is characterized by biochemical or diagnostic changes, despite testosteronemia levels similar to those after castration. The presentation of hormone refractory prostate cancer (HRCP) is rising with the increasing incidence of prostate cancer coupled with a prognosis of greater life expectancy.

HRCP could soon represent the most common cancer in the male population. The clinical variability, the lack of consensus on patients' eligibility for starting a different treatment, and the response criteria seen in literature have made it difficult to evaluate the impact of treatments.

However, there is now a consensus on defining HRCP when starting a second line hormonal therapy and a chemotherapy. HRCP is defined as three consecutive PSA increases of more than 50% of the nadir level occurring at least 2 weeks apart and a confirmed castrated level of testosterone (< 50ng/ml). This should be assessed after withdrawal of the antiandrogen (AW) for at least 4-6 weeks.

A second line hormonal treatment is available with Ketoconazole, aminoglutethimide, corticoids, and estrogens acting as adrenal steroidogenesis inhibitors and could induce a response in HRCP.

Some tumour prostatic cells may remain sensitive to small amounts of androgen products from the adrenal gland. Chemotherapy is introduced when there is a state of HRCP and the second line hormone therapy has failed.

Docetaxel plus prednisone is actually the preferred option for most patients with HRCP. An overall survival of 19 months can be achieved with docetaxel/prednisone. Despite this, there is a need to improve on this survival benefit because the relapse-free survival among responders is often short (6 months) and patients often have progression of their cancers leading to death. There are novel, promising treatment options for metastatic androgen independent prostate cancer, but they don't improve survival significantly and are very toxic drugs.

For this reason dutasteride has been utilized after failures of conventional treatment with second line hormone therapy and chemotherapy. There are multiple pharmacological bases that demonstrate the efficacy of dutasteride against HRCP.

This study examines the pharmacological basis and effect of the dual inhibitor dutasteride on HRCP. Dihydrotestosterone (DHT), catalyzed by the intracellular enzyme 5a-reductase (5aR), is a key step in normal prostate function. Furthermore, ex vivo studies have demonstrated that DHT has great stimulatory effect on prostate tumour growth compared with testosterone.

There are two well-characterized 5aR isoenzymes, 5aR1 and 5aR2, which are encoded by two distinct genes, SRD5A1 and SRD5A2, respectively, and located on separate chromosomes. Dutasteride inhibits both 5aR1 and 5aR2 to a similar extent (IC50 6nmol/l and 7 nmol/l, respectively). A number of studies have shown that 5aR1 expression is greater in prostate cancer, compared with benign tissue, at both the messenger RNA (mRNA) level and at the protein level, whereas 5aR2 expression and activity are decreased. Higher levels of both isoenzymes in recurrent and metastatic prostate cancer after androgen deprivation, compared with primary cancer, may reflect an adaptive or selective mechanism that amplifies the remaining androgen signal. Although prostate cancer that does not respond to androgen withdrawal is often described as "androgen independent," it appears that tumour growth is still mediated by the androgen receptor (AR), albeit via mechanisms that are not necessarily blocked by androgen deprivation therapy. The mechanisms could be as follow:

1) High-level amplification of the AR may be a compensatory response to androgen deprivation (in about 30% of cases).

2) Gain-of-function mutations, which enable the AR to bind ligands, other than testosterone or DHT, from patients with castration-recurrent cancer.

3) Upregulation of gene expression in androgen synthesis in bone marrow metastases of HRCP, including the 5aR1-coding gene SRD5A1.

4) Significant levels of estrogen alpha receptor appear as a late event in tumour progression because the most significant levels have been detected in metastatic and androgen insensitive lesions. Intracellular conversion of androgens to estrogens may contribute to the etiopathogenesis and to the progression of prostate cancer. Testosterone can also be aromatized to estradiol by aromatase. The combined treatment with 5aR and Aro inhibitors results in a strong decrease in cell proliferation.

5) Fatty acid Synthase activity is increased in HRCP, and its higher expression correlates with poor prognosis. Dutasteride inhibits FASN mRNA, protein expression, and enzyme activity in prostate cancer cells. In conjunction with down-regulation FASN activity, dutasteride induces apoptosis in LNCaP cells by activating genes in the TNFa pathway, such as BNIP3 and TNFRSF10B, leading to caspace 3/7 activation.

These putative mechanisms are consistent with the idea that dual 5aR inhibition may be valuable in the management of HRCP. A combination of androgen deprivation with dual 5aR1 and 5aR2 inhibition could inhibit tumour growth by reducing intracellular DHT levels beyond what can be achieved by androgen deprivation alone. The rationale for such an enhancement is that standard androgen ablation decreases testicular testosterone production but does not completely eliminate prostate cancer tissue testosterone content. Thus in the androgen depressed environment induced by standard androgen ablation, local 5a-reduction within metastatic prostate cancer cells amplifies the remaining androgen signal. Such androgenic amplification can be inhibited by simultaneous use of a dual 5a-reductase inhibitor.

In this study, eligibility criteria included: histological diagnosis of prostate adenocarcinoma with metastases, a serial rising PSA value on > 3 occasions and at least 2 weeks apart, or radiologically detected new or extensive lesions, a castration level of serum testosterone while receiving hormonal therapy, a Karnofsky performance status of > 40%, and a life expectancy of > 3 months.

As a primary hormonal therapy, all patients received LHRH analogues plus an antiandrogen. The antiandrogen was discontinued at least 4 weeks before administration of chemotherapy or ketaconazole plus hydrocortisone. One refused chemotherapy. Dutasteride therapy started only after treatment failure of chemotherapy or ketoconazole plus hydrocortisone and consisted of PSA elevation on > 3 occasions and at least two weeks apart or radiologically detected new or extensive lesions.

In general, patients underwent physical examinations and laboratory studies, including complete blood cell count, blood chemistry, and PSA at a minimum of every 4 weeks. Post therapy PSA decline was used to determine primary response to therapy. Both a PSA decline of > 50% and a PSA decline of > 75% were confirmed by a second PSA evaluation at least 4 weeks later.

Patient response was assessed in terms of bone pain by comparing the analgesic dose at the time of the lowest PSA level after therapy and the pretreatment dose. All patients were evaluated by CT scan or bone scan every 2 months.

The treatment, which was administered on an outpatient basis, was comprised of dutasteride 0.5 mg twice daily. All patients received an LHRH analogue continued therapy.

Mean follow-up was 9 months (4-21 months). Their median time to PSA disease progression was 6.9 months (ranging from 0-21 months).

Six patients had a PSA decline of > 75% and 4 patients had a PSA decline of > 50%. A greater decline in the PSA level was found to correlate with a longer median time to PSA disease progression. Two patients showed an increasing PSA during dutasteride therapy, and they died at 6 and 10 months. These patients were treated previously with Ketocanazole plus Hydrocortisole and docetaxel plus prednisone. Of the other 6 patients, 4 presented a stable PSA, while the PSA levels of the other 2 actually increased. No response was observed to bone scan or TC. Patients' response to PSA was associated with reduction to analgesic doses.

Other studies with more patients and a control arm are necessary to establish the real role of dutasteride in the treatment of HRCP.

Written by Fabio Arena, MD, as part of Beyond the Abstract on UroToday.com

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