Deferred combined androgen blockade therapy using bicalutamide in patients with hormone-refractory prostate cancer during androgen deprivation monotherapy

OBJECTIVE: To assess the effect of adding bicalutamide on serum prostate-specific antigen (PSA) levels in patients with hormone-refractory prostate cancer (HRPC) during androgen deprivation monotherapy (ADMT). PATIENTS AND METHODS: Forty-four patients with HRPC were treated with deferred combined androgen blockade (CAB) therapy, administering bicalutamide 80 mg once daily. HRPC was defined biochemically as three consecutive rises in PSA level during ADMT. The treatment response was defined as a > or = 50% decline in PSA levels. Prognostic values of various pretreatment variables for responsiveness to deferred CAB were determined statistically. When the disease relapsed during deferred CAB, bicalutamide was discontinued and the patients were evaluated for the antiandrogen withdrawal syndrome (AWS). RESULTS: Of the 44 patients, 29 (66%) had a PSA response; the median PSA failure-free survival was 9.2+ months. Biopsy Gleason score was the only pretreatment variable predictive of a PSA response (mean Gleason score 7.9 in responders and 8.7 in nonresponders). The PSA doubling time (PSA-DT) was the only statistically significant variable of PSA failure-free survival in a multivariate analysis. The 1- and 2-year PSA failure-free survival rates were 43% and 31% in patients with a PSA-DT of >4 months, while it was 21% and none, respectively, in those with a PSA-DT of <4 months. Responders to deferred CAB had a statistically longer cancer-specific survival than nonresponders. None of 20 patients who were evaluated for AWS had the condition. CONCLUSIONS: Deferred CAB therapy using bicalutamide is effective in patients with progression during ADMT, particularly in those with lower Gleason score tumours or a longer PSA-DT. AWS after deferred CAB is uncommon.     

A re-assessment of the role of combined androgen blockade for advanced prostate cancer

Combined androgen blockade is a controversial topic, which has arguments both for and against. It is revisited by the authors of this mini‐review, with a full discussion on the benefits and cautions with this approach. A wide range of other issues is also addressed in this section: bilateral testicular cancer, male‐factor infertility, and buccal mucosa urethroplasty. All of these are of interest to general urologists, as well as to those with a more specific area of interest.     

The androgen receptor pathway is by-passed in prostate cancer cells generated after prolonged treatment with bicalutamide

BACKGROUND: Experimental work in various prostate cancer models revealed that the androgen receptor is frequently upregulated and implicated in tumor progression. However, little attention has been paid to the androgen receptor-signaling pathway in the development of therapy resistance in patients who receive chronic treatment with a non-steroidal anti-androgen. METHODS: We have generated a novel subline, LNCaP-Bic, after prolonged treatment with androgen and bicalutamide in vitro. Proliferation of LNCaP-Bic cells in the absence or presence of androgen, tocopherol succinate, and/or bicalutamide was assessed by cell counting. Androgen receptor expression was determined by Western blot. Luciferase activity was measured in cells transfected with an androgen-responsive reporter. RESULTS: In basal conditions, proliferation of LNCaP-Bic cells increased more than threefold over that of control LNCaP cells. Neither synthetic androgen R1881 nor bicalutamide showed any effect on LNCaP-Bic growth in vitro. Androgen receptor expression did not differ between the cell subline generated in the presence of bicalutamide and parental LNCaP cells. The ability of R1881 to induce reporter gene activity in LNCaP-Bic cells was reduced by 56%. Tocopherol succinate caused inhibition of proliferation only in the parental cell line although the androgen receptor and prostate-specific antigen were down regulated by the vitamin E derivative in both parental LNCaP and LNCaP-Bic cells. CONCLUSIONS: Androgen receptor-mediated signal transaction is not enhanced in cells selected in the presence of bicalutamide. Our data may suggest that a more differentiated approach in targeting the androgen receptor is needed in prostate cancers that become resistant to classic endocrine treatment.     

Prostate-specific antigen flare phenomenon with docetaxel-based chemotherapy in patients with androgen-independent prostate cancer

OBJECTIVE

To evaluate the prostate‐specific antigen (PSA) ‘flare’ phenomenon in patients with androgen‐independent prostate cancer (AIPC) treated with docetaxel, as flare is a known effect of androgen‐deprivation therapy in hormone‐dependent prostate cancer.

PATIENTS AND METHODS

The charts of 56 patients who received docetaxel‐based chemotherapy in three different centres from August 1999 to August 2007 were reviewed retrospectively. The biochemical response was characterized according to the Bubley criteria. There was an immediate PSA response (PSA decline ≥ 50%) in 23 (41%) patients, PSA stabilization (PSA decline < 50%) in 16 (29%) and PSA progression in nine (16%). There was also a fourth response, i.e. PSA flare, defined as an increase in PSA level with no symptomatic progression, after starting docetaxel‐based chemotherapy administered every 3 weeks.

RESULTS

Eight (14%) patients with PSA flare were identified; all had osseous disease and five had additional soft‐tissue disease. The PSA flare lasted a median (range) of 21 (21–42) days and it spread over a median of 1 (1–2) cycles. The temporary PSA surge exceeded baseline values by a median (range) of 61.5 (12–404)%. There was a subsequent PSA response in six of the eight patients and PSA stabilized in the remaining two. Patients with flare received a median of 8.5 (5–12) treatment cycles, vs a median of 8 (2–12) in the immediate PSA response group (P = 0.103, Student’s t‐test). The Response Evaluation Criteria in Solid Tumors criteria evaluation showed one patient with a partial response and six with stable disease. The median survival of patients with PSA flare was 12.5 months, while that of the immediate PSA responders was 20.1 months (not statistically significant, P = 0.168, log‐rank test).

CONCLUSION

Of patients with AIPC, 14% had an initial PSA flare after starting docetaxel‐based chemotherapy. The occurrence of PSA flare had no effect on treatment duration or outcome. With lack of clinical progression, docetaxel‐based chemotherapy should be administered for at least two 3‐week cycles before further decisions are made about efficacy.     

Obesity is associated with castration-resistant disease and metastasis in men treated with androgen deprivation therapy after radical prostatectomy: results from the SEARCH database

Study Type – Prognosis (cohort series) Level of Evidence 2a What's known on the subject? and What does the study add? The incidence and prevalence of obesity in the USA and Europe is increasing. Higher body mass index is associated with a lower risk of overall prostate cancer diagnosis but also with an increased risk of high grade prostate cancer. Obese men undergoing primary therapy with radical prostatectomy or external beam radiation are more likely to experience a biochemical recurrence after treatment compared with normal weight men. Finally, obesity is associated with increased prostate‐cancer‐specific mortality. We hypothesized that obese men on androgen deprivation therapy may be at increased risk for prostate cancer progression. Previous studies have shown that obese men have lower levels of testosterone compared with normal weight men. Additionally, one previous study found that obese men have higher levels of testosterone on androgen deprivation therapy. Men with higher levels of testosterone on androgen deprivation therapy are at increased risk of prostate cancer progression. We found that men with higher body mass index were at increased risk of progression to castration‐resistant prostate cancer, development of metastases and prostate‐cancer‐specific mortality. When we adjusted for various clinicopathological characteristics, obese men were at increased risk of progression to castration‐resistant prostate cancer and development of metastases. The results of our study help generate hypotheses for further study regarding the mechanisms between obesity and aggressive prostate cancer.

OBJECTIVE

• ? To investigate whether obesity predicts poor outcomes in men starting androgen deprivation therapy (ADT) before metastasis, since previous studies found worse outcomes after surgery and radiation for obese men.

METHODS

• ? A retrospective review was carried out of 287 men in the SEARCH database treated with radical prostatectomy between 1988 and 2009.
• ? Body mass index (BMI) was categorized to <25, 25–29.9 and ≥30 kg/m2.
• ? Proportional hazards models were used to test the association between BMI and time to castration‐resistant prostate cancer (PC), metastases and PC‐specific mortality adjusting for demographic and clinicopathological data.

RESULTS

• ? During a median 73‐month follow‐up after radical prostatectomy, 403 men (14%) received early ADT.
• ? Among 287 men with complete data, median BMI was 28.3 kg/m2.
• ? Median follow‐up from the start of ADT was 52 months during which 44 men developed castration‐resistant PC, 34 developed metastases and 24 died from PC.
• ? In multivariate analysis, higher BMI was associated with a trend for greater risk of progression to castration‐resistant PC (P= 0.063), a more than threefold increased risk of developing metastases (P= 0.027) and a trend toward worse PC‐specific mortality (P= 0.119).
• ? Prognostic biomarkers did not differ between BMI groups.

CONCLUSIONS

• ? Among men treated with early ADT, our results suggest that obese men may have increased risk of PC progression.
• ? These data support the general hypothesis that obesity is associated with aggressive PC, although validation of these findings and further study of the mechanisms linking obesity and poor PC outcomes are required.

     

Commentary on maximal androgen blockade in prostate cancer: A theory to put into practice?

The population at risk of prostate cancer is on the increase, and so is public awareness of this disease. There has been an unresolved controversy surrounding the benefits of maximal androgen blockade (MAB) as a valid approach to treatment of non-curative prostate cancer since it was first proposed in 1945. How are we to interpret the data on MAB in order to give each patient the best advice on treatment? Studies of MAB using medical castration (luteinizing hormone-releasing hormone [LHRH] analogue plus antiandrogen) vs. LHRH analogues alone are inconclusive when viewed collectively, although the largest showed objective benefits for MAB. The remaining studies have insufficient power to show the expected effect size. Studies of MAB using surgical castration plus antiandrogen vs. surgical castration alone also gave inconsistent results, although a meta-analysis is in favor of MAB on objective criteria of response. Among trials of MAB using an LHRH analogue vs. surgical castration alone, one is positive and the remaining two are neutral for MAB. No study shows MAB to be worse than either medical or surgical castration alone. An overall meta-analysis shows a trend for benefit with MAB but is not statistically significant. The existing data have strongly suggested that there may be a particular benefit for certain subgroups of patients (including those with minimal disease) but numbers studied have been too small to allow valid conclusions. The INT 0105 trial in progress may permit firmer conclusions to be drawn on this and other questions. In the meantime one of the drawbacks to current MAB regimens is the exchange of modest clinical advantages for the side effects of nilutamide and flutamide. Given that the disease is noncurative, improved quality of life is the main goal of therapy, and excellent tolerability of treatment is fundamental to this. In a comparative trial, bicalutamide (Casodex) was more effective than flutamide (each in combination with an LHRH analogue) in terms of time to treatment failure and produced a significantly lower incidence of diarrhoea. In conclusion, the evidence supports early use of adequate hormonal treatment, and this should mean either medical or surgical castration, ideally augmented by an antiandrogen. Tolerability of the antiandrogen is a key consideration in gaining an improvement in quality of life with MAB. © 1995 Wiley-Liss, Inc.     

KDM5D predicts response to docetaxel chemotherapy in metastatic castration resistant prostate cancer patients

BackgroundThe administration of docetaxel chemotherapy is one therapeutic option to delay disease progression and increase overall survival in metastatic castration resistant prostate cancer (mCRPC). However, about 15% of patients are primary resistant to chemotherapy and hence would benefit from an alternative mCRPC treatment. Despite intensive research, there are no robust clinical validated biomarkers to predict mCRPC therapy response. Thus, the aim of the study was to determine KDM5D expression in archival radical prostatectomy specimens of patients medicated with docetaxel at time of mCRPC development in order to correlate KMD5D expression with treatment response.MethodsWe used in situ hybridization (ISH) (RNA scope 2.5 HD) to determine KDM5D expression in tissue samples of 28 prostate cancer patients. KDM5D status was correlated to chemotherapy response (PSA and radiographic response).ResultsData revealed that KDM5D is significantly overexpressed in tumor cells (P<0.0001) but also in benign cells (P<0.02) of those patients who responded to chemotherapy compared to non-responders.ConclusionsTo summarize, KDM5D is a promising novel biomarker predicting response to docetaxel chemotherapy already at the time of localized disease and thus potentially avoiding metastatic biopsies in the mCRPC stage of disease.     

Germline BRCA mutation does not prevent response to taxane-based therapy for the treatment of castration-resistant prostate cancer

Study Type – Prognosis (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? In the preclinical setting BRCA mutations appear to modulate response to chemotherapy, increasing sensitivity to platinums and increasing resistance to taxanes. Clinical data supports a greater platinum sensitivity among BRCA mutation carriers. This study suggests that BRCA mutation carriers may also respond to taxanes.

OBJECTIVE

? To investigate the relationship between BRCA mutation status and response to taxane‐based chemotherapy, since BRCA mutation carriers with prostate cancer appear to have worse survival than non‐carriers and docetaxel improves survival in patients with castration‐resistant prostate cancer.

PATIENTS AND METHODS

? We determined BRCA mutation prevalence in 158 Ashkenazi Jewish (AJ) men with castration‐resistant prostate cancer. Clinical data were collected as part of an institutional prostate cancer research database and through additional medical record review. ? Clinical records and DNA samples were linked through a unique identifier, anonymizing the samples before genetic testing for the AJ BRCA1/2 founder mutations. ? Response to taxane‐based therapy was defined by the prostate‐specific antigen nadir within 12 weeks of therapy.

RESULTS

? In all, 88 men received taxane‐based treatment, seven of whom were BRCA carriers (three BRCA1, four BRCA2; 8%). Initial response to taxane was available for all seven BRCA carriers and for 69 non‐carriers. ? Overall, 71% (54/76) of patients responded to treatment, with no significant difference between carriers (57%) and non‐carriers (72%) (absolute difference 15%; 95% confidence interval –23% to 53%; P= 0.4). ? Among patients with an initial response, the median change in prostate‐specific antigen was similar for BRCA carriers (?63%, interquartile range ?71% to ?57%) and non‐carriers (?60%, interquartile range ?78% to ?35%) (P= 0.6). ? At last follow‐up, all seven BRCA carriers and 49 non‐carriers had died from prostate cancer. One BRCA2 carrier treated with docetaxel plus platinum survived 37 months.

CONCLUSION

? In this small, hypothesis‐generating study approximately half of BRCA carriers had a prostate‐specific antigen response to taxane‐based chemotherapy, suggesting that it is an active therapy in these individuals.     

Combined androgen blockade in the management of advanced prostate cancer: A sensible or ostensible approach

BACKGROUND: To compare the efficacy of orchiectomy alone and orchiectomy plus flutamide in treating patients with advanced carcinoma prostate. MATERIALS AND METHODS: The study was initiated on 1 July 1997 and closed after enrolling 100 patients on 30 June 2000. Patients were prospectively randomized to orchiectomy alone (O) and orchiectomy plus flutamide (OF). A complete response (CR) was defined as the normalization of bone scans and serum prostate-specific antigen (PSA) levels returning to normal (< 4 ng/mL). A partial response (PR) was defined as a 50% reduction in metastasis mass compared to the initial study or a decrease in the PSA level of 50% of the initial value. Progressive disease (PD) was defined as the development of any new hot spot on bone scan or any increase in previously existing PSA level by 25%. RESULTS: A total of 100 patients were entered in the study. The maximum percentage change in PSA levels in both groups was found in the first 3 months after orchiectomy, that is, 95% and 97% for the O and OF groups, respectively. In more than 80% of the patients this decrease in PSA was maintained for 3 years. The mean percentage change at 3 years in the O and OF groups was 70% and 75% (P = 0.95), respectively, and the overall response rate (CR + PR) was 88.50% and 86.53% in the two groups, respectively (P = 0.85). The follow-up period ranged between 3 and 5 years (mean, 3.5 years). The mean time to progression was 27 and 29 months in the O and OF groups, respectively. The overall survival rate at 3 and 5 years in two treatment groups was 45.83% and 48.07%, 20.83% and 23.07% in the O and OF groups, respectively (P = 0.75). CONCLUSIONS: Maximum percentage decrease in PSA is seen within the first 3 months of therapy. Orchiectomy alone is as effective as combination therapy in decreasing serum PSA. Overall survival at 3 and 5 years in the orchiectomy only group was as good as that of combination therapy. These data suggest that the routine addition of flutamide to orchiectomy is not advisable.     

The role of docetaxel based therapy for prostate cancer in the era of targeted medicine

Docetaxel based chemotherapy has been shown to modestly extend life, relieve pain and improve the quality of life in patients with metastatic castration‐resistant prostate cancer. Current trials are attempting to build on the backbone of docetaxel by combining it with novel biological agents. Trials are also investigating the role of docetaxel for earlier stages of prostate cancer. No standard second‐line systemic therapy exists and such patients are candidates for clinical trials. The increased understanding of the mechanisms of progressive castration‐resistant prostate cancer is being translated into an increasing pipeline of novel therapies.     

Urologists and oncologists: adapting to a new treatment paradigm in castration-resistant prostate cancer (CRPC)

The treatment landscape for men with castration-resistant prostate cancer (CRPC) is undergoing significant changes; a redefinition of the respective roles of oncologists and urologists will probably occur. In addition, the advent of the multidisciplinary team or coordinated-care approach, which has been gathering momentum over the last decade, will become not simply a preference but a clear necessity. In the present review, we explore the current wave of new treatments and describe the possibility of more complex approaches to combined therapy. New treatment options include abiraterone acetate, cabazitaxel, MDV3100 (in development), radium-223 (in development) and sipuleucel-T. We also present the traditional roles of the urologist and oncologist in caring for patients with CRPC and discuss how these may change. Compounding the new potential for treatment success, as well as the complexity of therapeutic strategies, is the emergence of novel biomarkers to evaluate treatment efficacy and to assist in patient prognosis. The prospects for successful treatment of patients with CRPC have developed considerably so that these patients may soon have a reasonable expectation of therapeutic efficacy and meaningful extension of their lives.