Prostate-specific Antigen Doubling Research Articles

Evaluation of factors predicting response to abiraterone acetate in metastatic castration-resistant prostate cancer: A prospective study

Background/Objectives: In the current era, abiraterone acetate is mainstay of the treatment strategies of castration-resistant prostate cancer and proven to prolong overall survival. We aimed to prospectively identify factors associated with duration of response to abiraterone. Patients and methods: All metastatic castration-resistant prostate cancer patients eligible for abiraterone were included in the study from February 2019 till March 2020. All baseline data and potential factors associated recorded and follow-up with prostate-specific antigen (PSA), and required investigations were done at 1 month interval. Duration of PSA response was recorded, and patients were divided in five groups on the basis of duration of response. Univariate and multivariate analyses of potential factors were done, and data analysis was done with SPSS (Statistical Package for the Social Sciences) version 21.0. Results: In this study, after univariate analysis, seven factors were associated with longer duration of response to abiraterone. These were PSA at diagnosis (hazard ratio (HR) = −1.011 (95% confidence interval (CI) = 1.003–1.020), p-value = 0.008), PSA at start of abiraterone (HR = −1.018 (95% CI = 1.011–1.025), p-value = 0.0001), nadir PSA (HR = −1.063 (95% CI = 1.024–1.104), p-value = 0.001), prostate-specific antigen doubling (PSAD) time (HR = −0.745 (95% CI = 0.672–0.827), p-value = 0.001), raised alkaline phosphatase (ALP) (HR = −1.002 (95% CI = 1.001–1.003), p-value = 0.001), neutrophil/lymphocyte ratio (NLR) (HR = −2.16 (95% CI = 1.672–2.81), p-value = 0.001) and <5 bone metastasis (HR = −0.235 (95% CI = 0.130–0.422), p-value = 0.01). But after multivariate analysis, nadir PSA achieved, PSAD, NLR and ⩽5 bone metastasis were predictors of better response to abiraterone. Conclusion: This study had identified that less nadir PSA achieved, long PSAD time, low NLR and limited number of skeletal metastases were potential factors for better PSA response to abiraterone. Level of evidence: 1

Efficacy and safety of darolutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a sub-group analysis of the phase III ARAMIS trial

BackgroundDarolutamide, an oral androgen receptor inhibitor, has been approved for treating nonmetastatic castration-resistant prostate cancer (nmCRPC), based on significant improvements in metastasis-free survival (MFS) in the ARAMIS clinical trial. Efficacy and safety of darolutamide in Japanese patients are reported here.MethodsIn this randomized, double-blind, placebo-controlled phase III trial, 1509 patients with nmCRPC and prostate-specific antigen (PSA) doubling time ≤ 10 months were randomized 2:1 to darolutamide 600 mg twice daily or matched placebo while continuing androgen deprivation therapy. The primary endpoint was MFS.ResultsIn Japan, 95 patients were enrolled and randomized to darolutamide (n = 62) or placebo (n = 33). At the primary analysis (cut-off date: September 3, 2018), after 20 primary end-point events had occurred, median MFS was not reached with darolutamide vs. 18.2 months with placebo (HR 0.28, 95% CI 0.11–0.70). Median OS was not reached due to limited numbers of events in both groups but favored darolutamide in the Japanese subgroup. Time to pain progression, time to PSA progression, and PSA response also favored darolutamide. Among Japanese patients randomized to darolutamide vs. placebo, incidences of treatment-emergent adverse events (TEAEs) were 85.5 vs. 63.6%, and incidences of treatment discontinuation due to TEAEs were 8.1 vs. 6.1%.ConclusionsEfficacy outcomes favored darolutamide in Japanese patients with nmCRPC, supporting the clinical benefit of darolutamide in this patient population. Darolutamide was well tolerated; however, due to the small sample size, it is impossible to conclude with certainty whether differences in the safety profile exist between Japanese and overall ARAMIS populations.

Efficacy of androgen receptor antagonists in combination with androgen deprivation therapy in nonmetastatic, castration-resistant prostate cancer: A systematic review and meta-analysis of published phase III randomized controlled trials.

e17606 Background: Nonmetastatic, castration-resistant prostate cancer (nmCRPC) often heralds metastatic disease which is responsible for majority of the morbidity and mortality associated with prostate cancer. Hence, delaying metastasis is an expedient therapeutic goal for the patients with nmCRPC. Three androgen receptor (AR) antagonists — apalutamide, enzalutamide, and darolutamide — have been approved recently for nmCRPC on the basis of prolongation of metastasis-free survival. The purpose of our meta-analysis is to consolidate the efficacy data of AR-antagonists prolonging metastasis-free survival in nmCRPC. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE, and meeting abstracts as per PRISMA guidelines from inception until November 2019. Phase 3 RCTs using AR-antagonists for nmCRPC were included in the final analysis. We used generic inverse variance method and random effects model to calculate the pooled hazard ratio (HR) for distant metastasis or death with 95% confidence interval (CI). Heterogeneity was tested with I2 value and Cochran’s Q test. Results: Three phase 3 RCTs (ARAMIS, PROSPER, and SPARTAN) randomizing 2694 patients in the AR-antagonist arms and 1423 patients in the control arms are included in the final analysis. All studies enrolled only patients with prostate specific antigen (PSA) doubling time of 10 months or less. AR-antagonists used in the study arms were — ARAMIS: darolutamide, PROSPER: enzalutamide, and SPARTAN: apalutamide. Placebo was used in the control arms. All patients continued androgen deprivation therapy (ADT). Randomization was 2:1 in all studies. The pooled HR for distant metastasis or death was highly significant at 0.32 (95% CI: 0.25 - 0.41; P < 0.00001, I2 = 79%) in the favor of AR-antagonist arm in overall population. The pooled HR remained significant when patients were stratified according to PSA doubling time. For patients with PSA doubling time > 6months, the pooled HR was 0.34 (95% CI: 0.27 - 0.43; P < 0.00001, I2 = 0%); for patients with PSA doubling time ≤6 months, the pooled HR was 0.32 (95% CI: 0.25 - 0.41; P < 0.00001, I2 = 73%). Conclusions: Our meta-analysis demonstrated addition of AR-antagonists to ADT significantly prolongs the metastasis-free survival in patients with nmCRPC — an exciting new development in the management of prostate cancer.

Second-line Hormonal Therapy for the Management of Metastatic Castration-resistant Prostate Cancer: a Real-World Data Study Using a Claims Database

We evaluated the efficacy of second-line hormonal therapy for treatment of metastatic castration-resistant prostate cancer (mCRPC) in a real-world retrospective study. We conducted a population-based real-world cohort study of 258 mCRPC patients between 2014 and 2018 using the Chang Gung Research Database (CGRD) of Taiwan. The second-line hormonal therapy included abiraterone acetate and enzalutamide. The clinical efficacy outcomes were overall survival (OS) and prostate-specific antigen (PSA) doubling time. The median PSA level was also assessed. In total, 223 mCRPC patients who underwent second-line hormonal therapy met all of the inclusion and exclusion criteria for this study. Among them, 65 (29.1%) patients were in the PSA response group and 158 (70.9%) were in the non-response group. The median age was 72.9 years. The median OS was 12.3 months (range: 9.9–19.9 months) and 9.6 months (range: 5.3–15.9 months) in the response and non-response groups, respectively, and the respective PSA doubling times were 9.0 months (range: 4.4–11.6 months) and 3.9 months (range: 2.2–9.1 months), with a median follow-up period of 10.5 months. A significantly longer median OS was seen in the PSA response group. This real-world database study demonstrated that clinical outcomes of second-line hormonal therapy were better in patients with a PSA response. Further studies are warranted to achieve a better understanding of second-line hormonal therapy for mCRPC in Asian populations.

A randomized phase II study of apalutamide (APA), androgen deprivation therapy (ADT), or APA + ADT in patients (pts) with biochemically relapsed (BCR) prostate cancer (PC).

320 Background: While there is no standard therapy for BCR PC following local therapy, intermittent ADT is widely used. We evaluated utility of APA alone, ADT (luteinizing hormone–releasing hormone agonist [LHRHa]) alone, or APA + LHRHa in ADT-naïve BCR PC pts. Methods: Pts with BCR PC after primary definitive local therapy and prostate-specific antigen (PSA) doubling time (PSADT) ≤ 12 mo were randomized 1:1:1 to open-label 240 mg APA daily, LHRHa alone, or APA + LHRHa for 12 mo, followed by a 12-mo observation period off therapy. Pts were stratified by PSADT (< 6 vs 6-12 mo) and age (≤ 70 vs > 70 y). Primary end point: mean change from baseline (BL) in health-related quality of life (HRQoL) per Functional Assessment of Cancer Therapy-Prostate total score at 12 mo. Secondary end points included PSA nadir < 0.2 ng/mL by 7 mo, time to PSA progression (TTPpsa), and time to testosterone (T) recovery. Results: 90 pts (APA, n = 29; LHRHa, n = 30; APA + LHRHa, n = 31) were treated for median of 12 mo with similar distribution of BL characteristics across groups: 67% age ≤ 70 y; 67% PSADT < 6 mo. There was no significant difference in HRQoL in APA vs LHRHa at 12 mo, or between LHRHa vs APA + LHRHa groups. At median follow-up of 30-33 mo, TTPpsa in APA, LHRHa, and APA + LHRHa groups was 26 mo, 31 mo, and 36 mo, respectively. Compared to LHRHa alone, APA + LHRHa resulted in a trend toward improved TTPpsa (HR [95% CI] 0.56 [0.23-1.36], p = 0.196), and APA alone resulted in a trend for shorter TTPpsa (HR 1.09 [0.49-2.43], p = 0.824). PSA nadir < 0.2 ng/mL was reached in 89%, 89%, and 97% in APA, LHRHa, and APA + LHRHa pts. Median time to T recovery was similar in LHRHa and APA + LHRHa groups (23 mo vs 24 mo). Grade 3-4 adverse events (AEs) occurred in 17% of APA, 14% of LHRHa, and 29% of APA + LHRHa pts. The only grade 3-4 AE reported in > 1 pt per group was hypertension (APA, 3%; LHRHa, 0; APA + LHRHa, 13%). Conclusions: Addition of APA to LHRHa resulted in a trend for longer TTPpsa and a higher proportion of pts achieving optimal PSA nadir without significant difference in HRQoL or time to T recovery. Observed AEs were consistent with known safety profiles. Results support further evaluation of APA + LHRHa for a specified duration in BCR PC. Clinical trial information: NCT01790126.

Association of prostate specific-antigen doubling time (PSADT) with metastasis-free survival (MFS) and overall survival (OS) in non-metastatic castration-resistant prostate cancer (nmCRPC).

e16525 Background: For optimal nmCRPC management, it is important to assess the rate of disease progression and its predictors. MFS and OS endpoints are likely to be important determinants in evaluating the relative impact of treatments in nmCRPC patients. This study assessed the association of PSADT with MFS and OS in real world practice. Methods: A retrospective cohort study of men ≥18 years old was conducted using the Optum electronic health record (EHR) database (2007-2016). nmCRPC was defined as a prostate cancer diagnosis, no ICD-9/10 code or therapy indicating metastatic disease, a testosterone (T) level < 50 ng/dL (castrate level) and 2 rising PSAs (relative rise ≥25%; absolute rise ≥2 ng/mL above nadir) ≥1 week apart. Baseline PSADT, calculated from the PSA nadir until 2nd rise of PSA, was grouped into < 6, 6-18 or > 18 months. A Cox proportional hazard model was used to assess the association of baseline PSADT with MFS and OS, comparing PSADT < 6 and 6-18 months against PSADT > 18 months. Multivariable analysis was adjusted for age, race, comorbidity index score, T levels, therapy and bone scans before nmCRPC. A linear trend was tested by taking PSADT as a continuous variable (median value in each group) in the model. Results: A total of 901 patients were identified. Mean nmCRPC onset age was 76 years and mean follow-up time was 2 years. The median PSADT was 7 months, ranging from 0.5 to 267 months. During follow-up, 477 patients developed metastasis and 384 died. MFS was 89%, 60%, and 47% at year 1, 3 and 5, respectively. Men with PSADT < 6 and 6-18 months had ≥50% increased risk of shorter MFS than men with PSADT > 18 months; hazard ratios (HR) were 1.87 (95% confidence interval [CI]: 1.39-2.54) and 1.50 (95%CI: 1.11-2.04), respectively. OS was 87%, 64% and 57% at year 1, 3 and 5, respectively. Shorter PSADT was associated with shorter OS (p for trend < 0.001). Men with a PSADT < 6 months had a 2-fold increased risk for decreased OS (HR = 2.04, 95% CI: 1.44-2.90). Conclusions: Patients with nmCPRC with shorter PSADT had significantly shorter MFS and OS compared to those with longer PSADT. Baseline PSADT may serve as a predictor for nmCRPC progression.

Abstract B38: Pilot study of combination PSMA peptide and TARP peptide vaccine with poly-IC:LC adjuvant in HLA-A2 positive patients with elevated PSA after initial definitive treatment of prostate cancer

Abstract Background: For men with elevation of their prostate specific antigen (PSA) as the only sign of progression after initial definitive treatment, immune therapies could impact further disease progression. Epitopes from prostate-specific membrane antigen (PSMA) and T-cell receptor gamma alternate reading frame protein (TARP) capable of inducing in-vitro T-cell responses against prostatic tumors were used to synthesize the vaccine peptide. Each has a class II epitope and an HLA-A2 specific class I epitope. Working from prior studies showing responses of both cytotoxic T lymphocytes and T helper cells are more immunogenic than either alone, this prospective pilot study set to estimate the frequency that this peptide vaccine and poly-IC:LC adjuvant would induce ELISPOT identifiable improved titers. Secondary objectives included evaluation of the safety and toxicity of vaccination and impact on PSA change. Methods: Estimation of immunologic efficacy was accomplished using an ELISPOT assay of peripheral blood which assessed interferon-gamma secretion by activated T-cells in response to vaccination with PSMA-derived and TARP-derived peptides. Patients were vaccinated every 2 weeks for 8 total injections. Twenty-one patients had full ELISPOT data for analysis, which included pre-vaccination, on-treatment, and follow-up titers of PBMS alone, PSMA CD4, PSMA CD8, TARP CD4, and TARP CD8. Twenty-nine patients had PSA data, which were normalized by both date and PSA measurement. A table recorded the frequencies of adverse effects and dose-limiting toxicities (DLT). Results: Quarter-root power means were found to be the best for normalization of the ELISPOT results. The averaged PSMA CD4, PSMA CD8, TARP CD4, and TARP CD8 titers were all increased from baseline PBMC at time points 6 and 8. PSMA and TARP CD4 ELISPOT titers were also increased from PBMC baseline at time points 4 and 10. When restricted to time points 4, 6, and 8, the mean expression of PSMA CD4 and TARP CD4 compared to PBMC alone were significantly different, with a power mean fold increase of 2.70 (p=0.0001) and 2.45 (p=0.0006) respectively. The PSMA CD8 and TARP CD8 compared to PBMC were not significantly up during time points 4, 6, and 8. There were no DLT observed. Ten of the 29 patients had excellent stabilization of the PSA and did not have a PSA doubling before their last study visit; the last study date for this subset was a mean of 458 days from baseline PSA (55-613 days). Nineteen of the 29 patients had either a doubling of the PSA or proceeded to another therapy, occurring at a mean of 248 days (23-526 days). In these retrospectively divided subsets, the group with the longer PSA-doubling time appeared to have higher ELISPOT titer increases than the shorter PSA-doubling time group. Conclusions: A continued need for less intensive, nontoxic therapy such as vaccines exists in the treatment of prostate cancer patients, including those with biochemical failure. This pilot study showed feasibility of the class I + class II + poly-IC: LC combination protocol. Interestingly, significant increases in PMSA CD4 and TARP CD4 ELISPOT titers, as opposed to CD8 titer changes, were observed. A third of the subjects did not have PSA-doubling during the study period. The higher ELISPOT titers in the longer PSA-doubling time group also suggest an association, but not proof of causation, for better vaccine response and longer disease progression timelines. This pilot experience supports further clinical testing using peptide and poly-IC:LC vaccination combination therapies. Citation Format: Matthew Whitehurst, Xiuhua Zhao, Michael Schell, Esteban Celis, Andres Salazar, Mayer Fishman. Pilot study of combination PSMA peptide and TARP peptide vaccine with poly-IC:LC adjuvant in HLA-A2 positive patients with elevated PSA after initial definitive treatment of prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B38.

Poor association between the progression criteria in active surveillance and subsequent histopathological findings following radical prostatectomy

Objective. The objective of this study was to investigate the association between active surveillance (AS) progression criteria and histopathology features in subsequent radical prostatectomy (RP) specimens. Materials and methods. Of 229 patients managed on AS, 80 patients underwent RP, of whom 68 met at least one of the following three progression criteria: progression on rebiopsy, short prostate-specific antigen (PSA) doubling time (PSAdt) and increase clinical tumour category (cT). Patients revealing histopathological features in the RP specimens involving GS ≥ 7 (3 + 4) were considered to have achieved a potential survival gain from the procedure (timely RP). The association between the progression criteria and timely RP was analysed using univariate logistic regression analyses. Results. Of the 68 patients who met at least one of the progression criteria, 66% had timely RP features. Progression on rebiopsy was significantly associated with timely RP [odds ratio (OR) = 5.00, 95% confidence interval (CI) 1.51-16.51]. Although not statistically significant, progression defined by PSAdt was negatively associated with timely RP (OR = 0.36, 95% CI 0.13-1.00). Increase in cT showed no association with timely RP (OR = 1.17, 95% CI 0.35-3.87). Conclusions. A poor association was found between the progression criteria employed in the AS programme and histopathology features after subsequent RP. Only progression on rebiopsy was significantly associated with final histopathology.

A quantitative image analysis model of prostate biopsies for predicting clinical risk in men enrolled in an active surveillance program.

111 Background: Quantitative image analysis of the prostate needle biopsy (PNB) has proven to be a robust and predictive platform for prostate cancer (PCa) prognosis. We sought to determine the performance of quantitative metrics in identifying which patients enrolled in an active surveillance (AS) program are most likely to present with significant clinical risk, including subsequent biopsy Gleason grade (GG) upgrading and/or a short (less than 24 month) prostate-specific antigen (PSA) doubling time (PSADT). Methods: One hundred sixty two AS patients (median age 70, 94% cT1-T2a, 85% <=GS6, median PSA 5.9 ng/mL) with overall 8 year median follow up and available diagnostic PNB specimens were analyzed. Computerized image analysis derived quantitative biometric features representing PCa morphology and immunofluorescent (IF) biomarkers from the PNB. Multivariate models predicting either GG upgrading on a subsequent PNB or a PSADT less than 24 months were evaluated. The AUC/concordance index (CI), sensitivity, specificity and hazard ratio (HR) were used to assess performance. Results: Univariate distribution of selective features, notably expression levels of AR and Ki67, were reflective of a low risk cohort.A multivariate model with three quantitative imaging metrics was trained with a CI of 0.77. Men at high risk within 24 months of the PNB were identified with 80% sensitivity and 73% specificity, HR of 5.7. The most important feature measured the relative proportion of tumor epithelial nuclei that were both Androgen Receptor and alpha-methylacyl-CoA racemase positive. The other two features were morphological assessments of epithelial cellular area compared to luminal area. Of note, clinical features such as age, GG and PSA were not selected in competition with the imaging metrics. Conclusions: Quantitative image analysis of morphology and IF biomarker expression in the PNB outperformed standard clinical features in a multivariate model to accurately predict which AS patients are at risk for Gleason upgrading and/or a shortened PSADT. Identifying such patients may prove beneficial in the primary treatment decision process.

Prostate-Specific Antigen (PSA) Doubling Time at Time of PSA Relapse Is an Independent Predictor for Distant Metastasis and Survival After External Beam Radiation Therapy

Prostate-Specific Antigen (PSA) Doubling Time at Time of PSA Relapse Is an Independent Predictor for Distant Metastasis and Survival After External Beam Radiation Therapy

Overall survival in hormone-resistant prostate cancer patients with different transition of care within the Veterans Affairs (VA) system.

5091 Background: Prostate cancer patients with locally advanced /metastatic disease have a poor prognosis and although hormonal therapy can induce long-term remission, development of hormone-resistant prostate cancer (HRPC) is inevitable. The goal of this study is to evaluate overall survival in HRPC patients with different transition of care in the Veterans Affairs (VA) system. We hypothesized that prostate cancer patients with late referral to medical oncologists were more likely to have decreased overall survival. Methods: This is a retrospective, observational analysis of patients enrolled in the Veterans Health Administration system from October 2003 to March 2011. Patients were followed from initial evaluation and treatment by urology until an endpoint of death or the end of the study period. VA patients with a diagnosis of HRPC were identified; prostate specific antigen (PSA), medical and pharmacy records were collected. HRPC was defined as PSA doubling after treatment with hormonal therapy. Transition of care was defined as two encounters with the medical oncology service and at least one encounter was a medical oncologist. Three cohorts were created: patients transitioned to oncology before HRPC, those transitioned to oncology after HRPC, and patients who were never transitioned to oncology. Primary outcome was overall survival (OS). The Charlson score was utilized for comorbidity assessment. Statistical analysis was conducted using chi square test for categorical variables. Results: Total number of patients evaluated was 8,281; 2,168 in transition before HRPC (tbHRPC) cohort, 2,052 in transition after HRPC (taHRPC), and 4,061 patients that never transitioned (tnHPRC). The mean ages for the respective cohorts were: 69.35, 69.69, and 71.64. The Charlson comorbidity scores were 3.79 (tbHRPC), 3.06 (taHRPC), and 3.14 (tnHRPC); p-values < 0.05. Mortality rates among the cohorts were 57% tbHRPC, 69% taHRPC, and 62% tnHRPC; p-values <0.001. PSA doubling within 10 months were: 57% tbHRPC, 60% taHRPC, and 54% tnHRPC; p-values < 0.05. Conclusions: Overall survival was improved among prostate cancer patients that transitioned to oncology before becoming HRPC.

Associations of circulating 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and vitamin D pathway genes with prostate-specific antigen progression in men with localized prostate cancer undergoing active monitoring

Current diagnostic tests cannot differentiate the majority of prostate cancers with a low likelihood of progression from the minority with more aggressive potential. We examined whether the measures of vitamin D were associated with prostate-specific antigen (PSA) doubling time in men undergoing active monitoring. We examined the associations of circulating 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and vitamin D pathway polymorphisms with PSA doubling time in 490 men undergoing active monitoring for localized prostate cancer within a UK population-based cohort study [mean follow-up 4.4 years (range: 0.3-7.6)]. Repeat PSA measurements were analyzed using multilevel models. There was no evidence that circulating 25(OH)D levels, 1,25(OH)2D levels, or vitamin D pathway polymorphisms were associated with postdiagnosis PSA doubling time. Stratifying the results by prostate cancer grade at diagnosis (high grade or low grade) did not alter the results. We found no evidence that either circulating 25(OH)D, 1,25(OH)2D, or vitamin D pathway polymorphisms were associated with PSA doubling time in men undergoing active monitoring for localized prostate cancer. Future studies should examine the associations of variation in vitamin D with clinical outcomes (metastases and death).

High detection rate of significant prostate tumours in anterior zones using transperineal ultrasound‐guided template saturation biopsy

Study Type - Diagnostic (exploratory cohort) Level of Evidence 2b. What's known on the subject? and What does the study add? Men with persistent suspicion for prostate cancer after previous negative standard transrectal biopsy series are offered saturation biopsy either transrectally or transperineally to increase cancer detection rate. A high-risk group of men with at least two previous negative transrectal biopsies underwent transperineal template-guided saturation biopsy. Prostate cancer was detected in 26%, predominantly in the anterior zones. PSA velocity or doubling time were the most powerful factors to predict cancer. To evaluate the detection rate and the regional location of prostate cancer in men undergoing transperineal template-guided saturation biopsy (TTSB). In all, 92 consecutive men with at least two previous negative transrectal biopsy series who underwent a multiple-core prostate TTSB at our centre were included in the study. • Univariable and multivariable logistic regression analyses were used to address the relationship between parameters before TTSB and prostate cancer-detection rate. • Covariates consisted of age at biopsy, free and total prostate-specific antigen (PSA), prostate volume, digital rectal examination findings, histological findings on previous biopsy, PSA velocity (PSAV), PSA-doubling time (PSADT) and the number of previous negative biopsy sets. Prostate cancer was diagnosed in 26% of the men. • A median of 30 cores was taken by TTSB. • Adenocarcinoma in >2 cores was detected in 58.5% and Gleason score ≥7 was detected in 46% of the diagnosed men. • Most of the tumours (83.3%) were found in the anterior zones of the gland, with a significantly higher number of positive cores vs the posterior zones (mean 4.9 vs 1.5, P= 0.015). • PSADT and PSAV were the only independent predictors of prostate cancer detection at multivariate analyses with odds ratios of 0.71 (P= 0.014) and 1.58 (P= 0.025), respectively. TTSB has a high prostate cancer-detection rate, especially in the anterior zones. • Men after at least two previous negative transrectal biopsy series and persistent suspicion of prostate cancer, as evidenced by rapid PSA dynamics, should be offered TTSB.

General Commentary to the “Management of Biochemical Recurrence after Primary Localized Therapy for Prostate Cancer” by Darwish O. M. and Raj G. V.

TO THE EDITOR: In a recently published review on management of patients with biochemical failure (BF) following primary definitive therapy for localized prostate cancer (PCa), Darwish and Raj (2012) stated that following radical prostatectomy (RP) patients who are at high risk for recurrence after radiation therapy (RT), based upon a salvage nomogram, should be spared from this treatment modality justifying it by a range of toxicities it causes. Additionally, in the algorithm for management of BF after primary therapy they suggested that patients with a short prostate-specific antigen (PSA) doubling time (PSA-DT) and PSA > 10 ng/mL should not be offered salvage RT at all. Do these recommendations provide the optimal use of salvage RT following RP? Unfortunately, we feel that they do not. While we agree with the authors that patients with higher PSA at the time of radiation (RT), short PSA-DT, high Gleason score, and other “bad” prognostic characteristics do generally worse than patients without those features, it does not mean that salvage therapy should categorically not be discussed and potentially offered to patients at high risk of recurrence. As a matter of fact, in the study that was cited in the manuscript (Stephenson et al., 2007), select patients with some “bad” prognostic features did remarkably well after salvage RT. The 6-year progression-free estimate in patients with PSA-DT ≤ 10 months and GS 8–10 with low PSA was 41%. When looking at PSA-DT, in particular those with the shortest doubling time may be at the greatest risk for PCa-specific mortality (PCSM). Therefore, although salvage RT may be less likely to prevent recurrence in this group in the ones who are salvaged with RT the benefit may be profound. This is supported by the analysis from Trock et al. (2008) who found, in a retrospective analysis of 635 patients with BF after RP, that there was an increase in PCa-specific survival after salvage RT in patients with short PSA-DT ≤ 6 months only and not in those with a longer PSA-DT. Ina similar retrospective analysis of 432 patients with BF after RP, the beneficial effect of salvage RT on all-cause survival was more prominent in patients with PSA-DT ≤ 6 months than in patients with PSA-DT > 6 months, with adjusted hazard ratios of 0.35 (95% CI 0.17–0.72, p = 0.042) and 0.6 (95% CI 0.37–0.98, p = 0.04), respectively (Cotter et al., 2011). All these data suggest that salvage RT is effective and local control is still important in many patients with short PSA-DT, and PSA-DT should not be used to select patients that will not receive RT. As a result the suggestion by Darwish and Raj to avoid salvage RT in these patients would potentially deprive those with the greatest relative benefit in regard to PCSM and overall survival from receiving this therapy. Similarly, we disagree with the authors that “every salvage local therapy…for patients with BF is associated with a significant risk of complications…” Late complications after adjuvant or salvage RT are well documented from prospective randomized trials and from retrospective series. The rate of severe side-effects ranges from low (all grade 3–4, ≤5%; Bolla et al., 2005; Pearse et al., 2008) to very low (<1%; Feng et al., 2007; Wiegel et al., 2009) and should not preclude caretakers from offering this life-saving treatment to their patients. While every treatment decision should be based on patient’s preferences and informed consent, one should remember how little benefit from toxic antineoplastic therapies some patients will accept, when it is their only chance for cure. When considering adjuvant chemotherapy for early breast cancer (with less impressive HR for all-cause mortality (Early Breast Cancer Trialists’ Collaborative Group, 2005), and whose toxicities include death, life-threatening infections, neuropathy, cardiomyopathy, secondary cancers, infertility etc., a 1%-improvement in the chance of cure, or additional life expectancy of 6 months were found to be sufficient by 50% of women to decide that adjuvant chemotherapy was worthwhile (Duric and Stockler, 2001). For a man with a rising PSA after RP the use of salvage RT is the only potentially curative therapy, it can be delivered with a low risk of long-term toxicities, and should be discussed with patients as part of multidisciplinary management. Further, we would support enrollment of these men on a number of key clinical trials now being evaluated in this setting which aim to further refine the impact of the timing of RT, the use, and duration of androgen deprivation therapy, and the use of pelvic RT in this critical patient population (RADICALS; RTOG-0534). However, we would not, as the authors suggest, recommend that these patients be recommended to go directly to systemic therapy due to a misconception about both the potential benefits and likely harms of salvage RT.

Abstract 840: Pomegranate fruit extract inhibits prostate carcinogenesis in the TRAMP mouse model

Abstract Pomegranate fruit extract (PFE) dubbed as “nature's power fruit” was found to prolong prostate specific antigen (PSA) doubling time in men with rising PSA after surgery and therapy and hailed as a promising non-toxic strategy for slowing the progression of prostate cancer (PCa). To ascertain conclusive evidence of the effects of PFE against PCa require its efficacy evaluation in animal models that closely emulate human disease. Here, we provide evidence of remarkable tumor growth inhibitory effects using TRAMP, an autochthonous transgenic mouse model that mimics progressive forms of human PCa. Mice were supplied with 0.1% and 0.2% PFE as the sole source of drinking fluid starting at the age of 6 weeks. This drinking regimen is based on the assumption that a typical healthy individual (70 kg) may be persuaded to drink 250 or 500 ml of PFE from one or two fruits, respectively. Animals were examined at 12, 20 and 34 weeks of age for prostate tumor growth. In water-fed group, 100% mice developed palpable tumors by 20 weeks of age compared to only 30% and 20% in the 0.1% and 0.2% PFE-fed groups, respectively as assessed by abdominal pelvic palpation, MRI and ultrasound based imaging. At 34 weeks of age palpable tumors were observed in 70% of 0.1% PFE fed and only 50% of 0.2% PFE-fed TRAMP mice. Compared to a median survival of 43 weeks in water-fed mice, PFE-fed mice exhibited significant increase in life span with 0.1% and 0.2% PFE-fed mice exhibiting median life expectancy of 73 and 92 weeks, respectively. The cumulative data on metastasis at 20 and 34 weeks of age in the water-fed group showed 30% and 90% incidence of invasive tumors, which had metastasized to the lungs and liver. In sharp contrast, in the 0.1% and 0.2% PFE-fed group, none of the 20 mice exhibited metastases to any of the distant organs studied at 20 weeks of age and only 20% mice exhibited metastasis at 34 weeks of age. PFE feeding resulted in significant decrease in hyperplasia in the genitourinary (GU) apparatus, especially in the seminal vesicles. A significant decrease in GU weight (∼68% in 0.1% PFE and ∼79% in 0.2% PFE) compared with the water-fed TRAMP group was observed. At 34 weeks of age prostates of PFE-fed TRAMP mice contained well-differentiated adenocarcinoma that occupied ∼20% at surface area, admixed with lesser amounts of moderately differentiated adenocarcinoma (&amp;lt;3% of surface area), histology that was comparable to controls at 12 weeks of age. Many of the PFE-fed animals had multiple foci of well differentiated carcinoma (10-20% of surface area) and some had poorly differentiated carcinoma. PFE feeding resulted in simultaneous and significant inhibition of the IGF-I/Akt/mTOR pathways in the prostate tissues and tumors. This is significant since such a combined inhibition is seen only with a combination of drugs and not with a single agent alone. We suggest that pomegranate juice be evaluated in clinical trials in patients at high risk for developing prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 840. doi:10.1158/1538-7445.AM2011-840

Role of circulating tumor cells (CTCs) in biochemical recurrence (BR) of prostate cancer.

60 Background: CTCs have an established role in the prognosis of metastatic prostate cancer. Little data exists regarding the role of CTCs in BR of prostate cancer. The aim of this study was to determine whether there is a correlation between the number of CTCs in men with BR with varying prostate specific antigen (PSA) and PSA doubling time (PSADT) categories. Secondary endpoints looking at correlation of the CTCs with clinical or laboratory factors (Gleason scores, testosterone, hemoglobin, alkaline phosphatase, BMI, imaging results) will also be assessed. Methods: BR was defined as patients (pts) who have undergone primary treatment with prostatectomy or radiation or both, with rise to &gt;/= 0.2 from a prior undetectable level for prior prostatectomy or &gt; 2 mg/dl rise from post-nadir radiotherapy. The study was powered to detect a Pearson correlation of .46 with a sample size of 36. Eleven of planned accrual goal of 36 pts were enrolled from May to September 2010. PSADT was obtained and correlated with the CTC values, categorized as PSADT of &lt; 3 months, 3-14.9 months and &gt; 15 months. CTCs were evaluated in 7.5 mL of peripheral blood using the CTC CellSearch test. Results: The median age for 11 patients was 75 y/o (range: 57-91) with a median PSA of 1.6 ng/mL (range 0.2-6.5) and testosterone levels of 309 ng/dL (range: 31–471). Gleason scores were 8 (n=1), 7 (n=5), 6 (n=2), 5 (n=3). Prostatectomy was the primary treatment in 6 pts, radiotherapy in 5 pts and Cyberknife in 1 pt. Median hemoglobin was 12.43 g/dL, BMI was 26.79 and alkaline phosphatase was 69 IU/L. PSADT varied between 3 to 55 months. All pts accrued had 0 CTC levels. The latter result translates into a 95% confidence interval upper bound of approximately .27 for the proportion of patients in this population who have non-zero CTC levels. Conclusions: Prostate cancer pts with BR have negative blood CTCs and does not appear to correlate with PSA or PSADT. However, the limited number of patients precludes sufficient interpretation at this time and further accrual is ongoing. The absence of CTC levels in this patient population, if supported through further data collection, could emerge as an important unanticipated finding from this study. Supported by IRG-08-091-01 from ACS to GWU Cancer Institute. No significant financial relationships to disclose.

Editorial Comment on: Current Applications for Prostate-Specific Antigen Doubling Time

[38] Valicenti RK, Desilvio M, Hanks GE, et al. Posttreatment prostatic-specific antigen doubling time as a surrogate endpoint for prostate cancer-specific survival: An analysis of Radiation Therapy Oncology Group Protocol 92-02. Int J Radiat Oncol Biol Phys 2006;66:1064–71. [39] Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25:2035–41. [40] Moul JW, Wu H, Sun L, et al. Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. J Urol 2004;171:1141–7. [41] Hanlon AL, Horwitz EM, Hanks GE, Pollack A. Short-term androgen deprivation and PSA doubling time: their association and relationship to disease progression after radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys 2004;58:43–52. [42] Sengupta S, Blute ML, Bagniewski SM, et al. Increasing prostate specific antigen following radical prostatectomy and adjuvant hormonal therapy: doubling time predicts survival. J Urol 2006;175:1684–90, discussion 1690. [43] Stewart AJ, Scher HI, Chen MH, et al. Prostate-specific antigen nadir and cancer-specific mortality following hormonal therapy for prostate-specific antigen failure. J Clin Oncol 2005;23:6556–60. [44] Rodrigues NA, Chen MH, Catalona WJ, Roehl KA, Richie JP, D’Amico AV. Predictors of mortality after androgen-depri-

Stratification of Patient Risk Based on Prostate-Specific Antigen Doubling Time After Radical Retropubic Prostatectomy

To assess the risk of local recurrence, systemic progression, and death from cancer among patients who experience biochemical relapse after radical retropubic prostatectomy and to stratify those patients by prostate-specific antigen (PSA) doubling time (DT). We identified patients who experienced biochemical recurrence (defined as a PSA level < or =0.4 ng/mL) after radical prostatectomy from January 1, 1990, to December 31, 1999, for prostate adenocarcinoma. The PSA-DT was calculated by log linear regression using all PSA values within 2 years of biochemical recurrence. Local recurrence- and systemic progression- free survival and cancer-specific survival were estimated using the Kaplan-Meier method and analyzed by the log-rank test and Cox models. Biochemical recurrence was noted in 1521 (27%) of 5533 men during the follow-up period. Of the 1064 patients with a calculable PSA-DT, 322 (30%) had a PSA-DT of less than 1 year, 357 (34%) had a PSA-DT of 1 to 9.9 years, and 385 (36%) had a PSA-DT of 10 years or more. Patients with a PSA-DT of 10 years or more were less likely to have a higher preoperative PSA level, Gleason score, advanced pathologic stage, and seminal vesicle invasion. Patients with a PSA-DT of 10 years or more were at low risk of local recurrence (hazard ratio [HR], 0.09; 95% confidence interval [CI], 0.06-0.14; compared with patients with a PSA-DT of <1 year), systemic progression (HR, 0.05; 95% CI, 0.02-0.13), or death from cancer (HR, 0.15; 95% CI, 0.05-0.43). Prostate-specific antigen DT is an independent predictor of clinical disease recurrence and mortality after surgical biochemical failure. Risk stratification into high-, intermediate-, and low-risk categories based on the PSA-DT provides helpful clinical information and assists in the development of salvage therapy trials.

Sipuleucel-T* [Provenge] prolongs prostate-specific antigen (PSA) doubling time in patients with androgen-dependent prostate cancer,

Sipuleucel-T* [Provenge] prolongs prostate-specific antigen (PSA) doubling time in patients with androgen-dependent prostate cancer,

Prostate Cancer Prevention and Finasteride

We assessed whether the association between the larger changes in prostate specific antigen and high grade prostate cancer observed in the Prostate Cancer Prevention Trial can explain the increased detection of high grade prostate cancer in men randomized to finasteride vs placebo. A literature review was performed to obtain evidence to develop a hypothesis that may explain the results of the Prostate Cancer Prevention Trial. On average finasteride halved prostate specific antigen. As shown by the Medical Therapy of Prostatic Symptoms study and Prostate Cancer Prevention Trial, it also decreased the annual median increase in prostate specific antigen from benign prostatic hyperplasia. Therefore, despite doubling prostate specific antigen during the first 3 years of the Prostate Cancer Prevention Trial, to have prostate specific antigen exceed 4 ng/ml and have a prostate biopsy recommended men receiving finasteride vs placebo required greater increases in prostate specific antigen, which was shown in the Prostate Cancer Prevention Trial to be associated with high grade disease (p < 0.001). Also, the decrease of the contribution to prostate specific antigen from benign prostatic hyperplasia by finasteride improved the performance characteristics of prostate specific antigen to detect Gleason score 7 or higher prostate cancer. By decreasing the contribution to prostate specific antigen from benign prostatic hyperplasia finasteride makes changes in prostate specific antigen more cancer specific. This effect may explain the increased detection of high grade prostate cancer in men randomized to finasteride in the Prostate Cancer Prevention Trial. How to best use prostate specific antigen to recommend biopsy in men on 5alpha-reductase inhibitors requires further study.