Androgen Deprivation In Patients Research Articles

Abstract C062: Metabolic rewiring: A role for adenosine-inosine axis in African-American prostate cancer

Abstract African-American (AA) men have a 60% higher incidence of prostate cancer (PCa) compared to European-American (EA) men. An understanding of the altered biological responses and the factors that lead to health disparity in PCa is unclear. Metabolism defines the physiological state of the cell and metabolic reprogramming is a hallmark of cancer. Thus, studying the metabolic landscape will be crucial for understanding the biological changes that might contribute to this disparity. Analysis of 190 metabolites across PCa/benign adjacent tissue pairs from ancestry typed AA and EA men done in our laboratory, revealed altered levels of nucleosides adenosine and inosine. High inosine to adenosine ratio was observed in AA men compared to EA men. In line with this, the enzyme adenosine deaminase (ADA), which converts adenosine to inosine was found elevated in AA men, potentially explaining the high inosine to adenosine ratio in AA PCa. The consequences of the accumulation of these metabolites on AA PCa progression are unknown. This study will address the knowledge gap on the effects adenosine-inosine alterations in AA PCa and attempt to dissect its role in effecting an aggressive phenotype in PCa. To determine the role of elevated ADA in PCa, it was overexpressed in AA(MDA-PCa-2A) and EA PCa (LNCaP) cell lines (termed ADA OE). Phenotypic examination of these cells revealed high ADA enzyme activity decreases the cell-ECM adhesion. Molecular analyses revealed that upon ADA OE there is a reduction in Tenascin C(TNC), a matrix protein known for its anti-adhesive properties. TNC-rich microenvironment facilitates reactive stromal induction and high motility. This TNC-mediated reprogramming enhances the metastatic ability and PCa progression in bone. TNC induction was observed in stromal cells (DPT44) upon treatment with ADA OE conditioned media and inosine addition. PCa progression on bone was assessed using a cancer cell-bone in vitro co-culture system. High inosine and adenosine levels enabled better attachment of PCa cells to the bone. These findings suggest that an altered adenosine/inosine axis could facilitate adhesion decrease and modulate the stromal microenvironment to aid in the metastatic dissemination and migration towards the bone. Adenosine-inosine alterations could serve as a biomarker for metastatic PCa. We will further analyze the inosine and adenosine levels in patient samples and correlate them with various clinical outcomes in PCa. Our study so far shows high inosine to adenosine ratio in biopsy positive patient samples compared to biopsy negative samples. Our next steps of analysis include correlating the metabolite levels with (i)Biochemical recurrence (BCr) (ii)Time to attaining castration resistance (iii)Time to metastasis (iv)Response to Androgen deprivation in patients after BCr. Based on our current findings, we expect the inosine to adenosine ratio in plasma or urine to serve as a predictive marker for PCa incidence or progression in AA men. In addition, the enzyme ADA could serve as a potential therapeutic target for AA PCa. Citation Format: Christy Charles. Metabolic rewiring: A role for adenosine-inosine axis in African-American prostate cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C062.

Abstract PO-152: Metabolic rewiring in African-American prostate cancer: A role for adenosine-inosine axis

Abstract African-American (AA) men have a 60% higher incidence of prostate cancer compared to European-American (EA) men and tend to have a more aggressive clinical outcome. An understanding of the altered biological responses and the factors that lead to health disparity in prostate cancer development and progression is unclear. Metabolism defines the physiological state of the cell and metabolic reprogramming is a hallmark of cancer. Thus, studying the metabolic landscape will be critical for understanding the biological changes that might contribute to this disparity. Analysis of 190 metabolites across prostate cancer/benign adjacent tissue pairs from ancestry typed AA and EA men performed in our laboratory, revealed altered levels of adenosine and inosine. High inosine to adenosine ratio is observed in AA men compared to EA men. In line with this finding, the enzyme adenosine deaminase (ADA), which converts adenosine to inosine was found elevated in AA men, potentially explaining the high inosine to adenosine ratio in AA PCa. The effects of these metabolic alterations on AA PCa progression are unknown. The current study will address the knowledge gap on the consequences of elevated ADA activity in AA PCa and attempt to dissect its role in effecting an aggressive phenotype in PCa. To determine the role of elevated ADA in PCa, it was overexpressed in ancestry-typed AA (MDA-PCa-2A) and EA PCa(LNCaP) cell lines (termed ADA OE). Phenotypic examination of these cells revealed increased ADA enzyme activity decreases the cell-ECM adhesion. Molecular analyses revealed a significant reduction in Tenascin C(TNC), a matrix protein known for its anti-adhesive properties. TNC is critical for modulating cell motility and adhesion. TNC is also a marker for the reactive stromal microenvironment. Therefore, we evaluated the effects of altered adenosine-inosine levels on stromal cells. TNC induction was observed in stromal cells upon treatment with ADA OE conditioned media and inosine addition. These molecular findings suggest that high ADA activity could facilitate adhesion decrease and modulate the stromal microenvironment to aid in the metastatic dissemination from the primary tumor. From a translational viewpoint, ADA enzyme activity could serve as a biomarker for metastatic prostate cancer. Therefore, we further look to analyze the inosine to adenosine levels in patient samples and correlate with various clinical outcomes in PCa. Our initial analysis reveals high inosine to adenosine ratio in biopsy positive patient samples compared to biopsy negative samples. Our next steps of analysis include correlating the enzyme activity with (i)Biochemical Recurrence(BCr) (ii)Time to attaining castration resistance in castration-sensitive patients (iii)Time to metastasis (iv)Response to Androgen deprivation in patients after BCr. Based on our current findings, we expect the inosine to adenosine ratio in plasma or urine to serve as a predictive marker for PCa incidence or progression in AA men. In addition, we expect ADA to serve as a potential therapeutic target for AA PCa. Citation Format: Christy Charles. Metabolic rewiring in African-American prostate cancer: A role for adenosine-inosine axis [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-152.

Can local treatment prolong the sensitivity of metastatic prostate cancer to androgen deprivation or even prevent castration resistance?

PurposeA number of observational clinical studies suggest that prior primary tumor treatment favorably influences the course of metastatic prostate cancer (PCa), but its mechanisms of action are still speculative. Here, we describe the long-lasting sensitivity to various forms of androgen deprivation in patients after radical prostatectomy (RP) for locally advanced PCa as one potential mechanism.MethodsA consecutive series of 115 radical prostatectomies after inductive therapy for T4 prostate cancer was re-analyzed, and long-term survival, as well as recurrence patterns and responses to different forms of hormonal manipulation, were assessed.ResultsThe estimated biochemical response-free, PCa-specific, and overall survival rates after 200 months were 20%, 65%, and 47% with a median overall survival of 156 months. The majority of patients, although not cured of locally advanced PCa (84/115), showed long-term survival after RP. PCa-specific and overall survival rates of these 84 patients with biochemical recurrence were 61% and 44% at 150 months. Long-term sensitivity to ADT was found to be the main reason for the favorable tumor-specific survival in spite of biochemical recurrence.ConclusionsSensitivity to primary or secondary hormonal manipulation was the main reason for the long-term survival of patients who had not been cured by surgery only. The results suggest that treatment of the primary tumor-bearing prostate delays castration-resistant PCa and enhances the effect of hormonal therapies in a previously unknown manner. The underlying cellular and molecular mechanisms need to be explored in more detailed analyses, which could profoundly impact treatment concepts of locally advanced and metastatic PCa.

Abstract PR17: Metabolic re-wiring in African-American prostate cancer: A role of adenosine-inosine axis

Abstract African-American (AA) men have a 60% higher incidence of prostate cancer compared to European-American (EA) men and tend to have a more aggressive clinical outcome. An understanding of the altered biological responses and the factors that lead to health disparity in prostate cancer development and progression is unclear. Metabolism defines the physiological state of the cell and metabolic reprogramming is a hallmark of cancer. Thus, studying the metabolic landscape will be critical for understanding the biological changes that might contribute to this disparity. Analysis of 190 metabolites across prostate cancer/benign adjacent tissue pairs from ancestry typed AA and EA men performed in our laboratory, revealed altered levels of nucleosides adenosine and inosine. High inosine to adenosine ratio is observed in AA men compared to EA men. In line with this finding, the enzyme adenosine deaminase (ADA), which converts adenosine to inosine was found elevated in AA men, potentially explaining the high inosine to adenosine ratio in AA PCa. The consequences of the accumulation of these metabolites on AA PCa progression are unknown. The current study will address the knowledge gap on the consequences of elevated ADA activity in AA PCa and attempt to dissect its role in effecting an aggressive phenotype in PCa. To determine the role of elevated ADA in PCa, it was overexpressed in ancestry-typed AA (MDA-PCa-2A) and EA PCa(LNCaP) cell lines (termed ADA OE). Phenotypic examination of these cells revealed increased ADA enzyme activity decreases the cell-ECM adhesion. This adhesion decrease is facilitated by a decrease in cell adhesion protein integrin β1 (ITGB1). Elevated ADA enzyme activity decreases cAMP which mediates this adhesion decrease by disrupting the Epac-Rap1 pathway. It is postulated that high inosine upon ADA OE activates adenosine receptors A1 and A3, which causes this decrease in cAMP levels. These molecular findings suggest that ADA-mediated adhesion decrease could facilitate metastatic dissemination from the primary tumor. From a translational viewpoint, ADA enzyme activity could serve as a biomarker for metastatic prostate cancer. Therefore, we further look to analyze the inosine to adenosine levels (ADA enzyme activity) in patient samples and correlate with various clinical outcomes in PCa. Our initial analysis reveals high inosine to adenosine ratio in biopsy positive patient samples compared to biopsy negative samples. Our next steps of analysis include correlating the enzyme activity with (i) Biochemical Recurrence (ii) Time to attaining castration resistance in castration sensitive patients (iii) Time to metastasis (iv) Response to Androgen deprivation in patients after BCr. Based on our current findings, we expect inosine to adenosine ratio in plasma or urine to serve as a predictive marker for PCa incidence or progression in AA men. In addition, we expect ADA to serve as a potential therapeutic target for AA PCa. Citation Format: Christy Charles, Jie Gohlke, Stacy Lloyd, Uttam Rasaily, James Henderson, Balasubramanyam Karanam, Brian Simons, Nora Navone, Rick Kittles, Stefan Ambs, George Michailidis, Nagireddy Putluri, Arun Sreekumar. Metabolic re-wiring in African-American prostate cancer: A role of adenosine-inosine axis [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PR17.

Integrating Quantitative Assays with Biologically Based Mathematical Modeling for Predictive Oncology.

SummaryWe provide an overview on the use of biological assays to calibrate and initialize mechanism-based models of cancer phenomena. Although artificial intelligence methods currently dominate the landscape in computational oncology, mathematical models that seek to explicitly incorporate biological mechanisms into their formalism are of increasing interest. These models can guide experimental design and provide insights into the underlying mechanisms of cancer progression. Historically, these models have included a myriad of parameters that have been difficult to quantify in biologically relevant systems, limiting their practical insights. Recently, however, there has been much interest calibrating biologically based models with the quantitative measurements available from (for example) RNA sequencing, time-resolved microscopy, and in vivo imaging. In this contribution, we summarize how a variety of experimental methods quantify tumor characteristics from the molecular to tissue scales and describe how such data can be directly integrated with mechanism-based models to improve predictions of tumor growth and treatment response.

68Ga]Ga-PSMA-11 PET before and after initial long-term androgen deprivation in patients with newly diagnosed prostate cancer: a retrospective single-center study

PurposeThe study aimed to evaluate the effect of androgen deprivation therapy (ADT) on PSMA imaging and its correlation to the PSA concentration by comparing qualitative and quantitative parameters: SUVmax, SUVmean, PSMA-derived tumor volume (PSMA-TV), total lesion PSMA (TL-PSMA) and molecular imaging (mi)PSMA score.MethodsRetrospective analysis of 21 therapy-naïve patients with oligometastatic prostate cancer (median age 70 years) who underwent either [68Ga]Ga-PSMA-11-PET/CT or -PET/MRI before initiation of (T1) as well as during ADT (T2). The median duration of ADT was 155 days (range 61–289 days). All lesions were analyzed using several qualitative and quantitative PET parameters.ResultsA total of 109 PSMA-positive lesions (24 intraprostatic, 56 lymphonodal and 29 osseous) were visually detected at any of the examinations, while at T2, two new bone lesions were detected in one patient. During ADT, all patients experienced a decrease in their PSA level (median: 29.1 before vs. 0.71 after; p < 0.001). During long-term ADT, a relevant decrease in lesion count occurred, especially in patients with a T2 PSA value < 1 ng/ml (median: 4 vs. 0.9; p = 0.007) and PSMA expression, which resulted in miN- and/or miM-downstaging in 11 patients (52.7%).All analyzed PET parameters correlated strongly with each other. The PSA level at T2 correlated modestly with the decrease in PSMA expression and its derived volumes.ConclusionPost-ADT scans detected, especially in patients with a residual PSA < 1 ng/ml, fewer PSMA-positive lesions with overall lower PSMA expression, regardless of primary tumor site or metastatic sites. None of the PET parameters has proven to be superior, as they all correlated modestly with the PSA value at T2. Thus, the simply acquirable miPSMA score seems to be the most suitable for evaluating the effect of ADT on PSMA expression.

21 The Eldorado Study: A Phase II Randomised Study of Chemo-Radiation and Long-Term Androgen Deprivation in Patients with High-Risk Prostate Cancer. A Re-Analysis of the Primary Endpoint

21 The Eldorado Study: A Phase II Randomised Study of Chemo-Radiation and Long-Term Androgen Deprivation in Patients with High-Risk Prostate Cancer. A Re-Analysis of the Primary Endpoint

The Eldorado Study: A Phase II Randomized Study of Chemo-Radiation and LONG-TERM Androgen Deprivation in Patients with High-Risk Prostate Cancer. a RE-Analysis of the Primary Endpoint

The Eldorado Study: A Phase II Randomized Study of Chemo-Radiation and LONG-TERM Androgen Deprivation in Patients with High-Risk Prostate Cancer. a RE-Analysis of the Primary Endpoint

Phase 2 Randomized Study of Radiation Therapy and 3-Year Androgen Deprivation With or Without Concurrent Weekly Docetaxel in High-Risk Localized Prostate Cancer Patients

Docetaxel improves survival in patients with metastatic prostate cancer. This randomized phase 2 trial aimed to assess the activity of weekly docetaxel with radiation therapy (RT) plus androgen deprivation in patients with high-risk localized prostate cancer. The study examined the benefit of 9 weekly docetaxel administrations to RT plus 3years of luteinizing hormone-releasing hormone analogues. A total of 132 patients were recruited for the study. Patients' characteristics included T3-T4 stage (81.1%), Gleason score ≥8 (77.3%), prostate-specific antigen level >20ng/mL (28.9%), and pN+ (18.2%). All patients included in the trial received either the standard-of-care control arm with luteinizing hormone-releasing hormone analogues plus RT (arm A) or the experimental arm (RT+9 weekly cycles of docetaxel+3years of androgen deprivation therapy, arm B). The primary objective was to achieve a high percentage of patients who were free of biochemical recurrence within 5years of randomization. Secondary endpoints included biochemical recurrence-free survival (BRFS), progression-free survival (PFS), overall survival (OS), clinical response rate, biochemical response rate, and toxicity. No difference between the arms of the study was found in biochemical recurrence (93.4% at 60months for arm A vs 85.3% for arm B; P=.3297). PFS at 60months was 93.4% and 83.7% in arms A and B, respectively (P=.2532). Five-year survival was 93.3% (95% confidence interval, 83.1-97.45) in arm A versus 93.6% (83.8-97.55) in arm B; median PFS and OS have not been reached. Prostate-specific antigen level ≤0.2ng/mL at 3months after the end of treatment was seen in 81.25% of patients in arm A compared with 90.48% of patients in arm B (P=.2028). BRFS was not significantly different between treatment arms. Diarrhea was the main nonhematologic toxicity. Long-term follow-up has not yet been enough to meet median PFS and OS. Concurrent weekly docetaxel can be administered safely with standard doses of RT without a significant increase in the toxicity profile. No statistically significant differences for 5-year BRFS, PFS, and OS have been observed when docetaxel was added to conventional treatment.

Glycosylation is an Androgen-Regulated Process Essential for Prostate Cancer Cell Viability

Steroid androgen hormones play a key role in the progression and treatment of prostate cancer, with androgen deprivation therapy being the first-line treatment used to control cancer growth. Here we apply a novel search strategy to identify androgen-regulated cellular pathways that may be clinically important in prostate cancer. Using RNASeq data, we searched for genes that showed reciprocal changes in expression in response to acute androgen stimulation in culture, and androgen deprivation in patients with prostate cancer. Amongst 700 genes displaying reciprocal expression patterns we observed a significant enrichment in the cellular process glycosylation. Of 31 reciprocally-regulated glycosylation enzymes, a set of 8 (GALNT7, ST6GalNAc1, GCNT1, UAP1, PGM3, CSGALNACT1, ST6GAL1 and EDEM3) were significantly up-regulated in clinical prostate carcinoma. Androgen exposure stimulated synthesis of glycan structures downstream of this core set of regulated enzymes including sialyl-Tn (sTn), sialyl LewisX (SLeX), O-GlcNAc and chondroitin sulphate, suggesting androgen regulation of the core set of enzymes controls key steps in glycan synthesis. Expression of each of these enzymes also contributed to prostate cancer cell viability. This study identifies glycosylation as a global target for androgen control, and suggests loss of specific glycosylation enzymes might contribute to tumour regression following androgen depletion therapy.

Adverse Health Events Following Intermittent and Continuous Androgen Deprivation in Patients With Metastatic Prostate Cancer.

Although intermittent androgen-deprivation therapy (ADT) has not been associated with better overall survival in prostate cancer (PC), it has the potential for lower adverse effects. To our knowledge, the incidence of long-term adverse health events has not been reported. To examine long-term late events in elderly patients randomized to intermittent or continuous ADT to determine whether late cardiovascular and endocrine events would be lower in patients treated with intermittent ADT. This was a secondary analysis of a multicenter clinical trial using linkage between patient data from S9346, a randomized SWOG trial of intermittent vs continuous ADT in men with metastatic PC, and corresponding Medicare claims. Intermittent or continuous ADT. The main outcome was to identify long-term adverse health events by treatment arm. Patients were classified as having an adverse health event if they had any hospital claim--or at least 2 physician or outpatient claims at least 30 days apart--for any of the following diagnoses: ischemic and thrombotic events, endocrine events, sexual dysfunction, dementia, and depression. To incorporate time from beginning of observation through evidence of an event, we determined the cumulative incidence of each event. Competing risks Cox regression was used, adjusting for covariates. In total, 1134 eligible US-based male patients with metastatic PC were randomized to continuous vs intermittent ADT in the S9346 trial. A total of 636 of trial participants (56%) had at least 1 year of continuous Medicare parts A and B coverage and no health maintenance organization participation. The median age was 71.3 years. The most common long-term events were hypercholesterolemia (31%) and osteoporosis (19%). The 10-year cumulative incidence of ischemic and thrombotic events differed by arm; 24% for continuous and 33%for intermittent ADT (hazard ratio, 0.69; P = .02). There were no statistically significant differences by arm in any other adverse health events. Contrary to our hypothesis that intermittent ADT would reduce long-term health-related events compared with continuous ADT, we found that older men assigned to intermittent ADT had no apparent reduction in bone, endocrine, or cognitive events and an increased incidence of ischemic and thrombotic events. clinicaltrials.gov Identifier: NCT00002651.

Benefits of intermittent/continuous androgen deprivation in patients with advanced prostate cancer.

Background and aimsIn 1941 Huggins described the effect of castration on prostate cancer. gonadotropin-releasing hormone (GNRH) analogues were introduced in 1985. Complete androgen blockade (association of GNRH analogue with antiandrogen) was introduced by Fernand Labrie to achieve suppression of suprarenal testosterone. Long time androgen deprivation lead to androgen independence of the prostate cancer cell.Our principal aim was to demonstrate longer survival rates on prostate cancer patients with intermittent androgen deprivation.Methods82 patients in the Urology Department of Vasile Goldis West University Arad were included into two groups, with continuous and intermittent androgen deprivation.Treatment efficiency was assessed by the level of testosterone and PSA.Adverse events (AE) and serious adverse events were reported according to Common Terminology Criteria of Adverse Events (CTCAE) of the National Cancer Institute (NCI).ResultsEvolution towards castrate resistant prostate cancer: 12.5% from the intermittent androgen deprivation group and 23.8% from the continuous androgen deprivation groupMortality rate: 15% of patients from the intermittent androgen deprivation group; 19% of patients from the continuous androgen deprivation groupConclusionsBetter quality of life (Qol) in periods without treatment due to testosteron recovery;Less AE’s and metabolic syndrome (MS) related complications;Better survival and longer time of disease control andCost reduction.

Intermittent Versus Continuous Androgen Deprivation in Patients with Metastatic Prostate Cancer: Review

Intermittent Versus Continuous Androgen Deprivation in Patients with Metastatic Prostate Cancer: Review

Testosterone levels in metastatic castration-resistant prostate cancer (mCRPC).

191 Background: It is common practice to continue anti-androgen therapy in terms of androgendeprivation when performing chemotherapy or androgendeprivation with new second generation therapeutic agents such as enzalutamide or abiraterone acetate. Clinical Studies aiming at the question whether continuation of conventional ADT is necessary in this setting are currently recruiting. In this study we analyzed androgen deprivation in patients with mCRPC under chemotherapy and second generation androgen suppression. Methods: Out of 620 screened patients a total of 36 patients with continuous testosterone monitoring and mCRPC underwent therapy with docetaxel, abiraterone acetate, enzalutamide, carboplatin, carbozantinib or cabazitaxel and were evaluated. Data were gathered from our center over a median follow up period of 27.8 (0.6 - 65.1) month. A cutoff of 0.5 ng/dL was used to discriminate patients according to testosterone castration levels. Statistical evaluation was performed applying Kaplan Meier survival estimates, Cox regression and log rank test. Results: Median follow up was 26.2 month (range 1.4 - 64.8 month). Mean patient age was 70.9 years (range 51 - 86 years). The mean testosterone concentration in our cohort was 0.5 ng/dL. Serum testosterone levels varied greatly: ranging from 0 to 16 ng/dL. A total of 18 patients died during follow up. Median survival over all patients according to Kaplan-Meier survival estimation was 38.7 month (95% CI: 31 - NA month). Median survival for patients with testosterone levels below and above 0.5 ng/dL were 48.67 and 18.13 month respectively (log rank test: p = 0.0029). In Cox regression analysis, the hazard ratio for risk of death for patients with testosterone concentrations &gt; 0.5ng/dL was 6.03 (95% CI: 1.5 - 25, p - 0.0132). For the covariates PSA velocity, patient age and primary Gleason score there was no significant effect on risk of death (p = 0.0597, 0.5006, 0.7354). Conclusions: In patients with mCRPC i.e rising PSA or progression under androgen deprivation, conventional suppression of testosterone levels still represents a vital factor for overall survival even at the mCRPC stage and under therapy with second line anti hormonal therapeutic medication and chemotherapy.

Mechanisms of resistance to intermittent androgen deprivation in patients with prostate cancer identified by a novel computational method.

For progressive prostate cancer, intermittent androgen deprivation (IAD) is one of the most common and effective treatments. Although this treatment is usually initially effective at regressing tumors, most patients eventually develop castration-resistant prostate cancer (CRPC), for which there is no effective treatment and is generally fatal. Although several biologic mechanisms leading to CRPC development and their relative frequencies have been identified, it is difficult to determine which mechanisms of resistance are developing in a given patient. Personalized therapy that identifies and targets specific mechanisms of resistance developing in individual patients is likely one of the most promising methods of future cancer therapy. Prostate-specific antigen (PSA) is a biomarker for monitoring tumor progression. We incorporated a cell death rate (CDR) function into a previous dynamical PSA model that was highly accurate at fitting clinical PSA data for 7 patients. The mechanism of action of IAD is largely induction of apoptosis, and each mechanism of resistance varies in its CDR dynamics. Thus, we analyze the CDR levels and their time-dependent oscillations to identify mechanisms of resistance to IAD developing in individual patients.

Are PSA baseline levels an indicator for suitability of intermittent androgen deprivation in patients with PSA relapse after radical prostatectomy?

136 Background: Intermittent androgen deprivation (IAD) for prostate cancer patients is currently discussed as a treatment option to improve quality of life and to delay hormone resistance. So far only limited data are available indicating whether certain subgroups of patients with PSA relapse without local recurrence after radical prostatectomy are best suited for this therapy. Methods: In a prospective randomized phase III trial, men with unfavourable prognostic factors and a systemic PSA progression (PSA ≥ 1ng/ml) following an initial fall to &lt; 0.5 ng/ml within 3 months after radical prostatectomy were enrolled. They underwent a 6-months androgen deprivation (AD) induction phase with a microencapsulated leuprorelin acetate 3-month depot formulation plus an overlapping antiandrogen to prevent tumor flare-up. Achieving a PSA level &lt; 0.5 ng/ml, they were randomized to either an IAD treatment arm or to continuous AD. In the IAD arm, retreatment was started when PSA rose to ≥ 3 ng/ml. During Off-Treatment-Time (OTT) PSA and Testosterone were controlled on a monthly basis. Results: Analysis of the first IAD cycle, confined as induction phase + OTT, revealed two subgroups of patients with a cycle length ≤ 15 months (group 1) and ≥ 20 months (group 2) respectively. This was due to a significant difference in the time from testosterone normalization (≥ 2.3 ng/ml, TN) to an increased PSA-value ≥ 3 ng/ml. See Table. Conclusions: Our data show a significant (p=0.001) relationship of low PSA baseline levels to delayed biochemical PSA progression during OTT. Thus IAD might be most suitable for patients with low PSA baseline levels leading to a slow increase of PSA after TN during OTT, providing time to improve quality of life and delay potential hormone resistance. Further large scale studies will be necessary to confirm our findings. Clinical trial information: AP 06/95.[Table: see text]

Preliminary quality-of-life outcomes for SWOG-9346: Intermittent androgen deprivation in patients with hormone-sensitive metastatic prostate cancer (HSM1PC)—Phase III.

4571 Background: The relative quality of life (QOL) for patients with newly diagnosed, metastatic prostate cancer, treated with intermittent androgen deprivation (IAD) has been assumed and hypothesized, yet never compared in a well-powered randomized trial (RT) to continuous androgen deprivation (CAD). SWOG-9346 provided such a RT in which to test QOL differences between CAD and IAD in men with metastatic prostate cancer. Methods: Patients were randomized to CAD or IAD. Patients completed the SWOG QOL Questionnaire (SF-20/SF-36, Symptom Distress Scale, treatment-specific symptoms, global QOL) at randomization and months (mo) 3, 9, and 15 post-randomization. Five QOL change scores at one time point (mo 3) were designated as primary for the QOL endpoint and are reported in this abstract: impotence, libido, energy/vitality (E/V), physical function (PF), and emotional function (EF). Significance level was adjusted for 5 comparisons (used p=0.01). Results: 615 patients in the CAD arm and 633 in the IAD arm completed the QOL questionnaire at baseline. Change between baseline and 3 months differed for the two arms with CAD reporting statistically significantly more impotence and less libido than IAD. EF was also slightly better for the IAD arm. Conclusions: These results indicate better sexual function in men receiving IAD versus CAD through post-randomization month 3. Additional benefits for IAD may include better PF, E/V and EF. Ongoing analyses will address the role of missing data, additional follow-up assessments, and resumption of therapy in the IAD arm. [Table: see text]

Outcome Predictors of Radical Prostatectomy Followed by Adjuvant Androgen Deprivation in Patients with Clinical High Risk Prostate Cancer and pT3 Surgical Margin Positive Disease

Patients with high risk prostate cancer with pT3 tumor and positive surgical margins have a high risk of biochemical failure after radical prostatectomy and adjuvant androgen deprivation therapy. Predictors of cancer related death in this patient group are necessary. We performed subset analysis of a prospective trial including 550 consecutive patients with preoperative high risk prostate cancer (prostate specific antigen greater than 20 ng/ml ± cT3/4 ± biopsy Gleason 8-10). Men who underwent radical prostatectomy and received continuous adjuvant androgen deprivation therapy for pT3a/b N0-1 positive surgical margin disease were included in the analysis, and none of the patients received neoadjuvant androgen deprivation therapy or adjuvant radiation therapy. Overall 173 of 550 patients (31.5%) with a median followup of 67 months met the study inclusion criteria. For these men the estimated 8-year prostate cancer specific and overall survival rates were 86.3% and 77.0%, respectively. Tumor stage and positive surgical margin at the bladder neck were independent predictors of prostate cancer specific survival and overall survival, and were used to substratify cases. Those with pT3b disease with positive surgical margins at the bladder neck had the highest risk of death (5-year cancer specific survival 60.0% and overall survival 52.3%), while pT3a disease (regardless of positive surgical margin location and lymph node invasion) and pT3b tumors with negative bladder neck margins had 8-year prostate cancer specific survival and overall survival rates of 92.0% and 84.9%, respectively. The results of this trial demonstrated the heterogeneity of high risk prostate cancer cases with T3 tumors and positive surgical margins. The presented substratification by tumor stage and positive surgical margin location identifies men at high risk for prostate cancer related death and might help in the design of adjuvant therapy trials.

The FinnProstate Study VII: Intermittent Versus Continuous Androgen Deprivation in Patients With Advanced Prostate Cancer

We conducted a randomized trial to compare intermittent and continuous androgen deprivation in patients with advanced prostate cancer. We studied time to progression, overall and prostate cancer specific survival, and time to treatment failure. Between May 1997 and February 2003, 852 men with locally advanced or metastatic prostate cancer were enrolled to receive androgen deprivation therapy for 24 weeks. Patients in whom prostate specific antigen decreased to less than 10 ng/ml, or by 50% or more if less than 20 ng/ml at baseline, were randomized to intermittent or continuous androgen deprivation. In the intermittent therapy arm androgen deprivation therapy was withdrawn and resumed again for at least 24 weeks based mainly on prostate specific antigen decrease and increase. There were 298 patients who did not meet the randomization criteria. The remaining 554 patients were randomized, with 274 (49.5%) to intermittent androgen deprivation and 280 (50.5%) to the continuous androgen deprivation arm. Median followup was 65.0 months. Of these patients 392 (71%) died, including 186 (68%) in the intermittent androgen deprivation arm and 206 (74%) in the continuous androgen deprivation arm (p=0.12). There were 248 prostate cancer deaths, comprised of 117 (43%) in the intermittent androgen deprivation and 131 (47%) in the continuous androgen deprivation arm (p=0.29). Median times from randomization to progression were 34.5 and 30.2 months in the intermittent androgen deprivation and continuous androgen deprivation arms, respectively. Median times to death (all cause) were 45.2 and 45.7 months, to prostate cancer death 45.2 and 44.3 months, and to treatment failure 29.9 and 30.5 months, respectively. Intermittent androgen deprivation is a feasible, efficient and safe method to treat advanced prostate cancer compared with continuous androgen deprivation.

131 Finnprostate study VII: Intermittent versus continuous androgen deprivation in patients with advanced prostate cancer

131 Finnprostate study VII: Intermittent versus continuous androgen deprivation in patients with advanced prostate cancer