Baseline PSA Doubling Time Research Articles

Increase of prostate-specific antigen doubling time predicts survival in metastatic castration-resistant prostate cancer patients undergoing radium therapy.

Radium-223 (Ra-223) is an important treatment modality for bone-dominant metastatic castration-resistant prostate cancer (mCRPC). However, there is currently a lack of effective markers to monitor treatment response during treatment. We aim to investigate the response in prostate-specific antigen doubling time (PSADT) as a potential marker for assessing Ra-223 treatment in mCRPC patients. We retrospectively collected data from mCRPC patients who underwent radium treatment at our institution between August 2020 and June 2023. Prostate-specific antigen (PSA) measurements prior to treatment and during treatment were collected. Baseline PSADT was calculated from PSA measurements prior to Ra-223 treatment; interim PSADT was calculated from PSA measurements before Ra-223 treatment and prior to the fourth course injection. Overall survival was calculated from the start of treatment to the date of death. Univariable and multivariable analysis using the Cox proportional hazards model were performed to examine the association of factors with overall survival. We included 35 patients from our institution, with a median overall survival of 13.3months. Eighteen (51.4%) completed all six courses of treatment. PSA dynamic response (interim PSADT > baseline PSADT or decreased PSA) was observed in 20 patients. Overall survival was associated with a PSA dynamic response (HR = 0.318, 95% CI 0.133-0.762, p = 0.010) when compared to patients without response. Dynamic changes in PSADT were associated with survival in mCRPC patients receiving radium therapy. Comparing interim and baseline PSADT could serve as a valuable marker for determining treatment benefits.

Real-world prostate-specific antigen (PSA) response and disease progression among patients with non-metastatic castration-resistant prostate cancer (nmCRPC) initiated on apalutamide (APA).

69 Background: For patients with nmCRPC, APA with androgen deprivation therapy is an important therapeutic option with demonstrated efficacy in improving metastasis-free survival (MFS), and other clinical outcomes. However, there is limited real-world information on these outcomes among patients with nmCRPC treated with APA. This study describes PSA response and MFS among patients with nmCRPC treated with APA in the United States as compared to the SPARTAN registrational trial. Methods: Clinical data from 2/2017 to 4/2022 collected from 77 community-based urology practices were used to evaluate patients with nmCRPC who received ≥1 APA dispensation (index date being the date of first dispensation). Patients were excluded if they had previously used another next-generation antiandrogen or had <12 months of pre-index clinical activity. PSA response was evaluated while on treatment and was defined as a post-index ≥90% decline (PSA90) in PSA from baseline (using the closest PSA value within 13 weeks prior to or on the index date) and was reported in patients with ≥1 post-index PSA test result by 3 months, 6 months, 12 months and overall. Disease progression was evaluated as MFS and defined as the time from index date to the occurrence of metastasis or death, whichever occurred first. Disease progression was described using Kaplan-Meier (KM) analysis by 6-month increments up to 24 months post-index. Results: A total of 406 patients with nmCRPC (mean age 78.8 years, 73% white, mean baseline PSA 9.0 ng/mL) were identified. Among 96 patients with available data, the mean (median) baseline PSA doubling time was 9.9 (7.5) months. The mean (median) treatment duration was 434 (305) days. PSA90 rates were 40% by 3 months, 51% by 6 months, 56% by 12 months, and 58% overall. KM rates for MFS were 95% at 6 months, 90% at 12 months, 82% at 18 months, and 75% at 24 months. PSA response and MFS for real-world patients were consistent with those observed from the SPARTAN trial. Conclusions: This real-world study of patients with nmCRPC demonstrates that APA treatment resulted in early, deep PSA responses, consistent with the SPARTAN trial. Moreover, MFS observed in the real-world was similar to that of the SPARTAN trial. [Table: see text]

Modeled Early Longitudinal PSA Kinetics Prognostic Value in Rising PSA Prostate Cancer Patients after Local Therapy Treated with ADT +/- Docetaxel.

Simple SummaryIn prostate cancer patients with rising prostate-specific antigens (PSAs) after primary local therapy, and at high risk of metastatic disease based on a high Gleason score or ISUP grades 4–5 and/or short PSA doubling time, androgen-deprivation therapy (ADT) was shown to be effective with or without salvage radiotherapy. In the present paper, the analysis of a phase III trial dataset comparing ADT +/− docetaxel demonstrates that longitudinal PSA kinetics during the first 100 days of treatment, assessed using mathematical modeling, is associated with patient prognosis. Indeed, multivariate analyses showed that the modeled PSA production rate constant KPROD, and the elimination rate constant KELIM, exhibited strong and independent prognostic values regarding PSA progression-free survival (PSA-PFS) and overall survival (OS), respectively. As it was shown with the longitudinal CA-125 kinetic in ovarian cancers, the modeled longitudinal PSA kinetics during the 100 days of treatment may represent a novel prognostic factor in patients with metastatic prostate cancers.Background: In metastatic prostate cancer (PCa) patients, androgen-deprivation therapy (ADT) combined with chemotherapy or next-generation androgen receptor targeted agents is a new standard treatment. The objective of the present study is to assess longitudinal PSA kinetics during treatment using mathematical modeling, to identify the modeled PSA kinetic parameters able to exhibit early prognostic/predictive values. Methods: Phase III clinical trial dataset (NCT00764166) comparing ADT +/− docetaxel in 250 locally treated patients for PCa with rising PSA levels, who were at high risk of metastatic disease was assessed. A kinetic-pharmacodynamic (K-PD) model was used to fit PSA kinetics during the first 100 treatment days, to estimate the modeled PSA production rate K (KPROD) and elimination constant rate K (KELIM). The prognostic value of these parameters, considered as categorized (favorable vs. unfavorable) covariates regarding PSA progression-free survival (PSA-PFS) and overall survival (OS), was assessed using univariate/multivariate analyses. Results: Data from 177/250 patients was assessed. KELIM exhibited a significant prognostic value regarding PSA-PFS and KPROD regarding OS (univariate analysis). In the PSA-PFS final multivariate model, KELIM and the primary therapy type were significant. The OS multivariate model integrated both KPROD and baseline PSA doubling-time. Conclusion: In this first study assessing the modeled PSA kinetics prognostic value in PCa patients treated with systemic treatments, KELIM and KPROD exhibited respective prognostic values regarding PSA-PFS and OS.

Prostate-specific antigen response among Black and non-Black patients with advanced prostate cancer treated with apalutamide in a urology setting.

124 Background: Apalutamide (APA) is approved to treat patients with non-metastatic castration-resistant prostate cancer (nmCRPC) or metastatic castration-sensitive prostate cancer (mCSPC) in the United States (US) but low enrollment of Black patients in clinical trials has led to limited clinical data about APA for this population. This study describes prostate-specific antigen (PSA) responses among Black and non-Black patients with nmCRPC or mCSPC treated with APA in a real-world community urology setting. Methods: Clinical data from 2/2018 to 3/2021 collected at 69 US urology practices were used to evaluate nmCRPC or mCSPC patients who received ≥1 APA prescription fill (index date). Baseline PSA was reported based with the most recent baseline PSA value and PSA doubling time (PSADT) in months (mo) was calculated in patients with at least 2 PSA tests before APA initiation. PSA response defined as the proportion of patients achieving either a reduction of 50% (PSA50) or 90% (PSA90) from baseline and was evaluated in patients with a PSA test result 8 weeks or later after initiating APA. Among patients with a response, the time from the index date to the response was also evaluated. Study results for Black and non-Black cohorts were summarized separately. Results: Data from 289 nmCRPC (19% Black) and 237 mCSPC (19% Black) patients were identified. Median baseline PSA, median baseline PSADT and post-index PSA responses are shown in Table. A PSA50 response was attained by numerically similar proportions of Black and non-Black patients with nmCRPC or mCSPC. A PSA90 response was observed in a numerically higher proportion of Black than non-Black nmCRPC patients. Median time to PSA50 and PSA90 was also similar between groups. Conclusions: This real-world study of nmCRPC and mCSPC patients demonstrates that PSA50 and PSA90 responses are achieved by high proportions of both Black and non-Black patients. Moreover, the PSA50 and PSA90 responses observed in this study are highly consistent with those observed in APA’s Phase 3 registrational trials for nmCRPC (SPARTAN)1 and for mCSPC (TITAN)2.

Abstract CT207: A phase II trial using grape seed extract for prostate cancer patients with non-metastatic PSA progression after local therapy

Abstract Prostate cancer patients (pts) with non-metastatic prostate specific antigen (PSA) progression after local therapy and a long PSA doubling time (PSADT) usually have a period of PSA observation prior to starting on androgen deprivation therapy (ADT). We report results of an investigator-initiated, IRB-approved Phase II clinical trial (CT.gov-NCT03087903) investigating grape seed extract (GSE) in pts with PSA-only recurrence after maximum local therapy for prostate cancer. Pts with baseline PSA ≥ 0.2 ng/mL and rising PSA on 2 separate occasions and no evidence of metastases were eligible. Pts with baseline PSADT < 4 weeks (if absolute PSA > 2 ng/mL) were excluded. Pts were given 150mg of GSE orally twice daily for 12 months. GSE was administered as a formulation Leucoselect Phytosome-Indena S.p.A. (~100% proanthocyanidins, enriched in lower procyanidin oligomers complexed with soy phospholipids, about 1:2.6 w/w), with increased bioavailability. Study endpoints included PSA response (defined as an increase in PSADT by 30%) and change in PSA velocity. PSA was checked at baseline, 6 weeks and 3, 6, 9, and 12 months after starting GSE. Pts were removed from the trial with clinical/radiographic progression or if PSADT was less than 3 months. Pts completed dietary surveys and provided biologic specimens for tissue banking. The association of time and PSA level was assessed using a mixed effect modeling approach with the intention of calculating the doubling time. The natural log of PSA was taken to satisfy the linearity assumption of this method. Notably, pts on observation with a rising PSA after treatment for prostate cancer could be accrued rapidly to clinical trials; 27 pts were screened for this clinical trial at two sites (between January 2018 - August 2018) with 20 pts registered and started on treatment. Median (range) age and baseline PSA of pts enrolled were 71 (60 - 83) and 2.65 (0.44 - 17.44), respectively. Mean pretreatment PSADT was 5.4 months. GSE was well tolerated without serious adverse effects. 8 patients were withdrawn early due to PSADT progression of <3 months. The remaining 12 patients completed 12 months of follow-up. Mean post-treatment PSADT was 6.4 months. 9 patients met the endpoint of a PSADT increase of 30% or more. Taken together these results indicate that 300mg of daily GSE may improve PSA kinetics in pts with a rising PSA after maximum local therapy. This work was supported by NCI P30 CA46934 Cancer Center Support Grant, Cancer League of Colorado, the Writer Foundation, and the Barbara and Richard Gardner Fund for Prostate Cancer Research. Citation Format: Paul Maroni, Elizabeth R. Kessler, Rodrigo Rodrigues-Pessoa, Andrew Nicklawsky, Thomas Flaig, Elaine Lam, Brandon Bernard, James Moore, Kyra Anderson, Dexiang Gao, Komal Raina, Rajesh Agarwal. A phase II trial using grape seed extract for prostate cancer patients with non-metastatic PSA progression after local therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT207.

830P - Synthetic DNA immunotherapy in biochemically relapsed prostate cancer

Background: INO-5150 (PSA and PSMA) +/- INO-9012 (IL-12), a synthetic DNA immunotherapy, was assessed for safety, immunogenicity and efficacy in biochemically recurrent prostate cancer patients (pts). Methods: Phase I, open-label, multi-center study in the US included pts with rising PSA after surgery and/or RT, PSA doubling time (PSADT) >3 months (mos), testosterone >150 ng/dL and no concurrent ADT. Safety, immunogenicity and efficacy (PSA kinetics, PFS) were evaluated in 4 treatment arms of 15 pts each. Arms A: 2mg INO-5150, B: 8.5 mg INO-5150, C: 2mg INO-5150 + 1mg INO-9012 and D: 8.5mg INO-5150 + 1mg INO-9012. Pts received 4 IM doses of vaccine followed by electroporation on day 0, wks 3, 12 and 24 and were followed for 72 wks. Results: 50/61 (82%) pts completed all visits and treatments were well tolerated with no safety concerns. Median PFS for overall population [N = 61, baseline (D0) PSADT range (mos) 1.5-217.1, median 9.8] and for a subset of pts with D0 PSADT ≤12mos (N = 36) has not yet been reached (FU 3-19 mos). 86% of pts with D0 PSADT ≤12 mos were progression free through 19mos FU. 27 out of 36 (75%) pts with D0 PSADT≤ 12 mos had disease stabilization at wks 27 evidenced by significant improvement in log2PSA change over time (slope) and PSADT from D0 (Slope=0.19 declined to 0.1, PSADT=5.3 improved to 10.1 mos, p = <0.0001). This effect was maintained at wk 72 (Slope=0.09, PSADT=10.6, p = <0.0001). Immunogenicity was observed in 77% (47/61) of pts by multiple immunologic assessments. Patient immunogenicity to INO-5150 as determined by CD38 and Perforin + CD8 T cell immune reactivity correlated with attenuated % PSA rise compared to pts without reactivity (p = 0.05, n = 50). Conclusions: INO-5150 +/- INO-9012 was safe, well tolerated and immunogenic. Clinical efficacy was observed in the patients with D0 PSADT≤ 12 mos as evidenced by a significant dampening of log2PSA change over time and increased PSADT up to 72 weeks FU. Additional genomic analyses are ongoing to further elucidate the correlation of immunologic efficacy and clinical benefit. (NCT02514213). Clinical trial identification: FDA IND number 15870. Legal entity responsible for the study: Inovio Pharmaceuticals, Inc. Funding: Inovio Pharmaceuticals, Inc. Disclosure: N. Shore: Consulting or advisory role for multiple pharmaceutical companies. E.I. Heath: Consulting or advisory role and honoraria or funding received for multiple pharmaceutical companies. H. Cheng, Y. Whang: Funding received from multiple pharmaceutical companies. K. Bhatt, M. Morrow, T. McMullan, K. Kraynyak, J. Lee, B. Sacchetta, L. Liu, S. Rosencranz, I. Csiki, M.L. Bagarazzi: Employee of the pharmaceutical company sponsoring this research trial. S.T. Tagawa, R. Tutrone, J. Garcia, W. Kelly: Consulting or advisory role and funding received from multiple pharmaceutical companies. All other authors have declared no conflicts of interest.

SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC).

161 Background: Pts with nmCRPC are at risk for developing metastatic disease and cancer-specific mortality. There are no approved treatments for nmCRPC. APA is an orally administered next-generation androgen receptor inhibitor with antitumor activity in CRPC. SPARTAN evaluated the effects of APA on metastasis-free survival (MFS) in men with nmCRPC. Methods: Pts with nmCRPC and prostate-specific antigen doubling time (PSADT) of ≤ 10 mos were randomized 2:1 to APA (240 mg QD) or PBO. The primary end point was MFS, defined as the time from randomization to first radiographic distant metastasis (per blinded central review) or death. Secondary end points included time to metastasis (TTM), progression-free survival (PFS), time to symptomatic progression (SymProg), and overall survival (OS). Pts were eligible to receive study-provided abiraterone acetate plus prednisone after developing distant metastases. Second progression-free survival (PFS2, the time from randomization to disease progression or death after first treatment for metastatic CRPC) was also evaluated. Results: 1207 pts were randomized. Baseline PSADT was &lt; 5 mos in both groups. APA decreased the risk of distant metastasis or death by 72% (HR = 0.28; 95% CI, 0.23-0.35; p &lt; 0.0001), with a median MFS of 40.5 vs 16.2 mos in the PBO group. Secondary end points (TTM, PFS, and SymProg) were all significantly improved. At an interim analysis for OS, there was a trend favoring APA. At a median follow-up of 20.3 mos, 61% of APA and 30% of PBO pts were still on treatment. Rates of discontinuation due to adverse events were low in both groups (10.7% APA, 6.3% PBO). Mean baseline health-related quality of life scores were maintained with treatment, with no difference between groups over time. Of those whose disease progressed, 80% of PBO and 56% of APA pts received therapy for metastatic CRPC. PFS2 was significantly longer for APA vs PBO. Conclusions: APA significantly improved median MFS by 2 years in men with nmCRPC. APA also significantly increased TTM, PFS, SymProg, and PFS2. APA was associated with improved OS. These results support the addition of APA to androgen deprivation therapy in men with nmCRPC. Clinical trial information: NCT01946204.

Muscadine Grape Skin Extract (MPX) in Men with Biochemically Recurrent Prostate Cancer: A Randomized, Multicenter, Placebo-Controlled Clinical Trial.

Purpose: MuscadinePlus (MPX), a commercial preparation of pulverized muscadine grape skin, was evaluated as a therapeutic option for men with biochemically recurrent (BCR) prostate cancer wishing to defer androgen deprivation therapy.Experimental Design: This was a 12-month, multicenter, placebo-controlled, two-dose, double-blinded trial of MPX in 125 men with BCR prostate cancer, powered to detect a PSA doubling time (PSADT) difference of 6 months (low dose) and 12 months (high dose) relative to placebo. Participants were stratified (baseline PSADT, Gleason score) and randomly assigned 1:2:2 to receive placebo, 500 mg MPX (low), or 4,000 mg MPX (high) daily. Correlates included superoxide dismutase-2 (SOD2) genotype, lipid peroxidation, and polyphenol pharmacokinetics.Results: The evaluable population included 112 patients, all treated for at least 6 months and 62% treated for 12 months. No significant difference was found in PSADT change between control and treatment arms (P = 0.81): control 0.9 months (n = 20; range, 6.7-83.1), low dose 1.5 months (n = 52; range, 10.3-87.2), high dose 0.9 months (n = 40; range, 27.3-88.1). One high-dose patient experienced objective response. No drug-related CTCAE grade 3-4 adverse events were seen. In a preplanned exploratory analysis, PSADT pre-to-post increase was significant in the 27 (26%) genotyped patients with SOD2 Alanine/Alanine genotype (rs4880 T>C polymorphism) on MPX (pooled treatment arms; 6.4 months, P = 0.02), but not in control (1.8 months, P = 0.25).Conclusions: Compared with placebo, MPX did not significantly prolong PSADT in BCR patients over two different doses. Exploratory analysis revealed a patient population with potential benefit that would require further study. Clin Cancer Res; 24(2); 306-15. ©2017 AACR.

Clinical variables associated with overall survival in metastatic castration resistant prostate cancer (mCRPC) patients treated with sipuleucel-T immunotherapy.

e16565 Background: Sipuleucel-T (Sip-T) is a cellular-based cancer immunotherapy for men with asymptomatic or minimally symptomatic mCRPC. Its approval was based on overall survival (OS) benefit in randomized placebo-controlled phase 3 trials. However, treatment was associated with PSA decline in only a small minority of pts. Understanding clinical factors predictive of OS may help to guide treatment decisions, including pt selection and timing of Sip-T relative to other therapies. Methods: This is a retrospective chart review of mCRPC pts treated with Sip-T at UCSF between April 2010 and April 2016. All pts completed 3 Sip-T infusions. Patients with localized prostate cancer treated with neoadjuvant Sip-T (NCT00715104) and pts with mCRPC treated with an ongoing phase 2 Sip-T/Ipilimumab trial (NCT01804465) were excluded. Kaplan-Meier method was used to estimate OS. The predictive value of candidate variables – including age, ECOG performance status (PS), Gleason score, metastatic volume, baseline PSA, baseline PSADT, prior abiraterone or enzalutamide, and prior chemotherapy – was assessed using univariate and multivariate Cox proportional hazard model. Results: Of 43 patients evaluated to date, 74.4% had ECOG PS 0, 88.4% had bone +/- nodal metastasis, 81.4% had low metastatic volume, 9.3% had prior abiraterone, 2.3% had prior enzalutamide, and 9.3% had prior chemotherapy. The median age was 69 years (range 53-85), median baseline PSA was 8.3 ng/mL (range 0.05-227.9) and median PSA doubling time (PSADT) was 3.9 mo (range 1.4-15.1). At a median follow-up of 21.4 mo, the median OS was 34.1 mo (95% CI 25.7-41.4). Univariate analysis showed that ECOG PS (HR 6.66, p &lt; 0.001) and PSA (log-transformed) (HR 3.36, p = 0.002) were significantly associated with OS. There was a trend towards worse OS with faster baseline PSADT (log-transformed) (HR 0.16, p = 0.11) and prior chemotherapy (HR = 4.13, p = 0.11). By multivariate analysis, ECOG PS, baseline PSA and baseline PSADT were statistically significant (p &lt; 0.05). Conclusions: In this ongoing retrospective cohort, ECOG PS, baseline PSA and baseline PSADT were associated with OS in mCRPC patients treated with Sip-T.

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 &lt; 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 &lt; 6, 6-18 or &gt; 18 months. A Cox proportional hazard model was used to assess the association of baseline PSADT with MFS and OS, comparing PSADT &lt; 6 and 6-18 months against PSADT &gt; 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 &lt; 6 and 6-18 months had ≥50% increased risk of shorter MFS than men with PSADT &gt; 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 &lt; 0.001). Men with a PSADT &lt; 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.

Denosumab and Bone Metastasis–Free Survival in Men With Nonmetastatic Castration-Resistant Prostate Cancer: Exploratory Analyses by Baseline Prostate-Specific Antigen Doubling Time

Denosumab, an anti-RANK ligand monoclonal antibody, significantly increases bone metastasis-free survival (BMFS; hazard ratio [HR], 0.85; P = .028) and delays time to first bone metastasis in men with nonmetastatic castration-resistant prostate cancer (CRPC) and baseline prostate-specific antigen (PSA) ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤ 10.0 months. To identify men at greatest risk for bone metastasis or death, we evaluated relationships between PSA and PSADT with BMFS in the placebo group and the efficacy and safety of denosumab in men with PSADT ≤ 10, ≤ 6, and ≤ 4 months. A total of 1,432 men with nonmetastatic CRPC were randomly assigned 1:1 to monthly subcutaneous denosumab 120 mg or placebo. Enrollment began February 2006; primary analysis cutoff was July 2010, when approximately 660 men were anticipated to have developed bone metastases or died. In the placebo group, shorter BMFS was observed as PSADT decreased below 8 months. In analyses by shorter baseline PSADT, denosumab consistently increased BMFS by a median of 6.0, 7.2, and 7.5 months among men with PSADT ≤ 10 (HR, 0.84; P = .042), ≤ 6 (HR, 0.77; P = .006), and ≤ 4 months (HR, 0.71; P = .004), respectively. Denosumab also consistently increased time to bone metastasis by PSADT subset. No difference in survival was observed between treatment groups for the overall study population or PSADT subsets. Patients with shorter PSADT are at greater risk for bone metastasis or death. Denosumab consistently improves BMFS in men with shorter PSADT and seems to have the greatest treatment effects in men at high risk for progression.

A pilot phase II study of digoxin in patients with recurrent prostate cancer as evident by a rising PSA.

5061 Background: Hypoxia-inducible factor 1α (HIF-1α) is a novel cancer drug target and inhibitors of hypoxia-response pathway are being developed. Digoxin and other cardiac glycosides were found to inhibit prostate cancer (PCa) growth via the inhibition of HIF-1α synthesis in mouse model. Epidemiologic data showed that use of digoxin in men was associated with a significant lower risk of development of PCa. We hypothesized that therapeutic dose of digoxin could inhibit human PCa growth and disease progression. Methods: Open label, non-placebo pilot study. Non-metastatic, biochemically relapsed PCa patients (pts) with prostate specific antigen doubling time (PSADT) of 3 -24 months and no hormonal therapy within the past 6 months were enrolled. All pts had testosterone &gt; 50 ng/dL at baseline. Digoxin was taken daily with dose titration to therapeutic level (0.8 – 2 mg/dl) and pts had routine follow-up that include cardiac monitoring with EKG. The primary endpoint was to evaluate the proportion of patients at 6 month post-treatment that had a PSADT &gt; 200% from the baseline. Results: Fifteen pts were enrolled into the study with 13 pts finishing the planned 6 months of treatment. Twenty percent (3/15) of the pts had PSA decrease &gt;25% from baseline. At 6 months, 7 of 15 (47%) pts had PSADT &gt; 200% of the baseline PSADT and were continued on study for an additional 24 weeks of treatment. Mean duration of digoxin treatment was 34.5 weeks. Digoxin was well tolerated with possible relation of one grade 3 back pain and one grade 2 hyperglycemia. No pts came off study due to cardiac reasons. Pre-and post-treatment PSA kinetics, vascular endothelial growth factors and other cytokines levels are being determined. Conclusions: Digoxin was well tolerated and showed a prolongation in the PSDAT in 47% of the patients. Digoxin may have biologic activity in men with androgen-dependent PCa but further controlled studies are required to confirm the results. Clinical trial information: NCT01162135.

958 CAN ANTIANDROGEN WITHDRAWAL THERAPY BE PERFORMED SAFELY FOR AGGRESSIVE PROSTATE CANCER?

INTRODUCTION AND OBJECTIVES: Antiandrogen withdrawal (AAWD) is a potential therapeutic maneuver for treating patients with castration-resistant prostate cancer (CRPC) who have undergone a combined antiandrogen blockade (CAB) therapy. However, clinicians are also concerned that, for patients with aggressive CRPC demonstrating a short PSA doubling time (PSADT), discontinuation of antiandrogens may result in even greater exacerbation of the disease. This study was designed to examine the safety of AAWD therapy. METHODS: We reviewed the medical records of patients with CRPC who received prior initial treatment with CAB therapy during the period of 2001-2011. In 95 patients, AAWD therapy (68 patients previously received bicalutamide, and 27 patients flutamide) for CRPC was performed, and we examined the changes in PSADT before and after AAWD. Serum PSA determinations were obtained 4 weeks before stopping antiandrogen therapy, immediately before (baseline PSA level), and every 4 weeks thereafter. RESULTS: A reduction in the serum PSA level after AAWD was observed in 29 of 95 patients (30.5%), and a greater than 50% decrease from the baseline serum PSA level was observed in 11 patients (10.5%). The median response duration in these 29 responders was 4.0 months. In the 66 non-responders, the mean PSADT before and after AAWD was 7.7 and 6.2 months, respectively. A shortening of PSADT after AAWD was observed in 37 patients (38.9%). Next, using a logistic regression model with stepwise forward selection, we performed univariate and multivariate analyses to identify predictors that have an influence on shortening of PSADT after AAWD (Table below). Interestingly, the results indicated that patients with a short PSADT (aggressive disease) before AAWD had a low risk of subsequent shortening of PSADT after AAWD. In 25 patients with baseline PSADT 2 months, a shortening of PSADT after AAWD was observed in only 3 patients (12.0%). Furthermore, 8 of the 25 patients (32.0%) responded to the AAWD therapy, and 2 patients (8.0%) achieved a greater than 50% decrease from the baseline PSA level. CONCLUSIONS: Our data indicate that patients with a short baseline PSADT (aggressive disease) had a low risk for worsening of the disease by AAWD, and we concluded that it should be recommended for all patients with CRPC before embarking on the next therapeutic maneuver.

A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer

Pomegranate juice has been associated with PSA doubling time (PSADT) elongation in a single-arm phase II trial. This study assesses biological activity of two doses of pomegranate extract (POMx) in men with recurrent prostate cancer, using changes in PSADT as the primary outcome. This randomized, multi-center, double-blind phase II, dose-exploring trial randomized men with a rising PSA and without metastases to receive 1 or 3 g of POMx, stratified by baseline PSADT and Gleason score. Patients (104) were enrolled and treated for up to 18 months. The intent-to-treat (ITT) population was 96% white, with median age 74.5 years and median Gleason score 7. This study was designed to detect a 6-month on-study increase in PSADT from baseline in each arm. Overall, median PSADT in the ITT population lengthened from 11.9 months at baseline to 18.5 months after treatment (P < 0.001). PSADT lengthened in the low-dose group from 11.9 to 18.8 months and 12.2 to 17.5 months in the high-dose group, with no significant difference between dose groups (P = 0.554). PSADT increases >100% of baseline were observed in 43% of patients. Declining PSA levels were observed in 13 patients (13%). In all, 42% of patients discontinued treatment before meeting the protocol-definition of PSA progression, or 18 months, primarily due to a rising PSA. No significant changes occurred in testosterone. Although no clinically significant toxicities were seen, diarrhea was seen in 1.9% and 13.5% of patients in the 1- and 3-g dose groups, respectively. POMx treatment was associated with ≥ 6 month increases in PSADT in both treatment arms without adverse effects. The significance of this on-study slowing of PSADT remains unclear, reinforcing the need for placebo-controlled studies in this patient population.

Effect of denosumab on prolonging bone-metastasis free survival (BMFS) in men with nonmetastatic castrate-resistant prostate cancer (CRPC) presenting with aggressive PSA kinetics.

4510 Background: Denosumab, an anti-RANK-ligand monoclonal antibody, has been shown to prolong BMFS by a median 4.2 months and with a 15% risk reduction vs. placebo in men with non-metastatic CRPC and baseline PSA value ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤10.0 months. To determine the efficacy of denosumab in men at greatest risk for bone metastases, we evaluated BMFS in a subset of men with PSADT ≤6 months (previously reported in Smith MR, et al: J Clin Oncol. 23:2918-2925, 2005). Methods: 1,432 men with non-metastatic CRPC (baseline medians: PSA: 12.3 ng/mL, PSADT: 5.1 months, ADT duration: 47.1 months) were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or placebo. The first patient enrolled February 2006; primary analysis cut-off was July 2010, when &gt;660 men had developed bone metastasis or died. The primary endpoint was BMFS (time to first bone metastasis or death from any cause). BMFS results are presented for men with baseline PSADT ≤6 months. Results: Median BMFS in the placebo group of men with PSADT ≤6 months was 6.5 months shorter than for the placebo group in the full population (18.7 months vs. 25.2 months), indicating that these men are at particularly high risk. In this group of men with PSADT ≤6 months, denosumab prolonged BMFS by a median of 7.2 months and with a 23% reduction in risk compared with placebo (Table). Conclusions: Patients with shortened PSADT are at higher risk of developing bone metastasis and denosumab is markedly effective at prolonging BMFS in this subset of patients. [Table: see text]

Overall survival (OS) prognostic factors in metastatic castrate-resistant prostate cancer (mCRPC) patients retreated with docetaxel (D).

e15213 Background: Until recently, few post-D treatment options existed for mCRPC patients (pts). In pts taken off of first-line D for reasons other than progressive disease (PD), retreatment with D at the time of PD was a commonly used strategy. While several prognostic nomograms have been developed for mCRPC patients, none have exclusively examined prognostic factors in D retreated patients. In the present study, we aimed to characterize baseline clinical factors associated with OS outcomes in D retreated mCRPC pts. Methods: Between 1/2007 and 10/2010, all mCRPC pts seen in the Indiana University Simon Cancer Center oncology clinics were approached for recruitment to the IRB approved biorepository protocol. Participants completed a demographic and clinical questionnaire and provided a blood sample. Only mCRPC pts retreated with D with confirmed dates for D first-line completion, D retreatment, and OS were included in this analysis. At D retreatment, patient age, Gleason Grade (GG), presence of pain, time to progression after first-line D therapy, visceral metastases, ECOG performance status, PSA, and PSA doubling time (PSAdt) were examined by Cox proportional hazards model for significant associations (p &lt; 0.05) with OS outcomes. Results: 30 mCRPC pts retreated with D were identified. Complete data were available on 22 pts which formed the analysis cohort. Demographics included: mean age – 69.1 yrs, Caucasian/African-American – 21/1, median GG 8, 55% pain present at baseline, median time from first-line D – 8.6 mo., 30% visceral mets, ECOG 0/1/2 – 3/17/2, mean baseline PSA – 536 ng/ml, mean baseline PSAdt – 2.7 mo. By Cox proportional hazards model, baseline PSA (p = 0.006) was significantly associated with D-retreatment OS with a trend toward significance in patients with pain at baseline (p = 0.059). No other significant associations were identified. Conclusions: Baseline PSA levels were significantly associated with OS outcomes in mCRPC pts retreated with D. Validation and examination of additional clinical variables is warranted in larger datasets.

Changes in PSA kinetics predict metastasis‐free survival in men with PSA‐recurrent prostate cancer treated with nonhormonal agents

Several phase II trials in men with noncastrate PSA-recurrent prostate cancer have assessed the impact of novel nonhormonal agents on PSA kinetics. However, it is unknown whether changes in PSA kinetics influence metastasis-free survival (MFS). We performed a retrospective post hoc analysis of 146 men treated in 4 phase II trials examining the investigational agents marimastat (a matrix metalloproteinase inhibitor; n = 39), imatinib (a tyrosine kinase inhibitor; n = 25), ATN-224 (a copper/zinc-superoxide dismutase inhibitor; n = 22), and lenalidomide (an antiangiogenic/immunomodulatory drug; n = 60). We investigated factors influencing MFS, including within-subject changes in PSA kinetics (PSA slope, doubling time, and velocity) before and after treatment initiation. After a median follow-up of 16.8 months, 70 patients (47.9%) developed metastases. In multivariable Cox regression models, factors that were independently predictive of MFS after adjusting for age and other clinical prognostic variables were baseline PSA doubling time (PSADT) (P = .05), baseline PSA slope (P = .01), on-study change in PSADT (P = .02), and on-study change in PSA slope (P = .03). In a landmark Kaplan-Meier analysis, median MFS was 63.5 months (95% confidence interval [CI], 34.6-not reached) and 28.9 months (95% CI, 13.5-68.0) for men with or without any decrease in PSA slope by 6 months after treatment, respectively. This hypothesis generating analysis suggests that within-subject changes in PSADT and PSA slope after initiation of experimental therapy may correlate with MFS in men with biochemically recurrent prostate cancer. If validated in prospective trials, changes in PSA kinetics may represent a reasonable intermediate end point for screening new agents in these patients.

Predictors of Unfavourable Repeat Biopsy Results in Men Participating in a Prospective Active Surveillance Program

Background Active surveillance (AS) protocols for low-risk prostate cancer (PCa) generally include repeat prostate biopsies at predefined follow-up intervals. Objective To study the outcome of routinely obtained 1-yr repeat biopsies and factors predicting reclassification to higher risk, to contribute to risk stratification for men on AS. Design, setting, and participants We analysed men with low-risk PCa (clinical stage ≤T2, prostate-specific antigen (PSA) ≤10 ng/ml, PSA density <0.2 ng/ml per millilitre, one or two positive biopsy cores, and Gleason score ≤6) who had been included in a prospective AS protocol. Interventions PSA was measured 3-monthly and the first volume-dependent repeat biopsy was scheduled 1 yr after diagnosis, independent of PSA doubling time (PSA-DT). Reclassification to higher risk disease on repeat biopsy was defined as Gleason score ≥7 or ≥3 positive cores. Measurements We analysed whether baseline patient characteristics and PSA-DT were associated with reclassification to more aggressive PCa on repeat biopsy. Results and limitations A first repeat biopsy was taken in 757 patients after median follow-up of 1.03 yr. The results of repeat biopsies were favourable (no or low-risk PCa) in 594 patients (78.5%) and led to reclassification of risk in 163 (21.5%). Analysis showed that reclassification to higher risk was significantly influenced by the number of initial positive cores (two vs one) (odds ratio [OR]: 1.8; p = 0.002) and higher PSA density (OR: 2.1; p = 0.003). The outcome was not significantly influenced by age, clinical stage, total number of biopsy cores, or PSA. Adding PSA-DT at time of repeat biopsy to the model showed PSA-DT <3 yr to be significantly associated with reclassification to higher risk (OR: 1.7; p = 0.015). Data on tumour involvement per biopsy core were not available. Conclusions Clinical features at baseline and during follow-up in our AS cohort are significantly associated with short-term reclassification to higher risk on repeat biopsy. These characteristics can potentially be used for risk stratification of men with PCa who are apparently at favourable risk. Trial registration The current program is registered at the Dutch Trial Register with identification number ID NTR1718 ( http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1718).

A phase II study of pomegranate extract for men with rising prostate-specific antigen following primary therapy.

4522^ Background: Pomegranate extract (POMx) demonstrates antitumor effects through antioxidants in prostate cancer (PCA). Prior work reveals an increase in PSA doubling time (PSADT) in a single arm study of pomegranate juice (POM) in PCA patients (pts) with a rising PSA after local therapy. We sought to determine the effects of 1 gram or 3 grams daily POMx on PSADT in a similar but more inclusive population of men seeking to defer androgen deprivation therapy. Methods: This multi-center, double bind phase II, dose-exploring trial randomized men with a rising PSA and without metastases to receive 1 gram or 3 grams of POMx, stratified by baseline PSADT and Gleason score, and with no restrictions for PSADT and no upper limit PSA value. Men were treated until progression or for 18 months. PSA levels were obtained every 3 months. This study was designed to detect a 6 month on study increase in PSADT from baseline on each arm. Results: 104 patients were enrolled and treated for up to 6 (92%), 12 (70%) and 18 months (36%). Median PSADT lengthened in the Intent to treat population (96% white, median age 74.5 years, median gleason score 7) from baseline 11.9 (range 1.6-54.6) compared to 18.5 (2-1523) months after treatment (p<.001).There was no significant treatment difference on PSADT between the dose groups (p=.920). Forty-three percent (41/95) of men had a post-treatment PSADT of more than 200% of baseline PSADT and no new metastases. Declining PSA levels were observed in 13 pts (13%) during the study. No significant changes occurred in testosterone in either group. Although no clinically significant toxicities were seen, mild to moderate diarrhea was seen in 8 percent of patients. Conclusions: POMx treatment significantly increased the PSADT by over 6 months in both treatment arms, with no effect on testosterone. This IND-conducted study confirms slowing of PSADT with POMx as was found with POM, yet in a more inclusive PCA patient population.

890 SENSITIVITY FACTORS ANALYSIS ON LOW DOSE KETOCONAZOLE PLUS PREDNISONE EFFECTIVE TREATMENT FOR CASTRATION RESISTANT PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced1 Apr 2011890 SENSITIVITY FACTORS ANALYSIS ON LOW DOSE KETOCONAZOLE PLUS PREDNISONE EFFECTIVE TREATMENT FOR CASTRATION RESISTANT PROSTATE CANCER Guo-Wen Lin, Xu-Dong Yao, Ding-Wei Ye, Bo Dai, and Yao Zhu Guo-Wen LinGuo-Wen Lin Shanghai, China, People's Republic of More articles by this author , Xu-Dong YaoXu-Dong Yao Shanghai, China, People's Republic of More articles by this author , Ding-Wei YeDing-Wei Ye Shanghai, China, People's Republic of More articles by this author , Bo DaiBo Dai Shanghai, China, People's Republic of More articles by this author , and Yao ZhuYao Zhu Shanghai, China, People's Republic of More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.756AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To explore whether there were some predictors of low dose ketoconazole(LDK) effective treatment for castration resistant prostate cancer(CRPC). METHODS 71 patients with CRPC were eligible for this retrospective study. They underwent previous hormonal therapy failure and 14 patients had been given chemotherapy based on docetaxel. At the baseline, serum PSA, testosterone and hemoglobin were detected. Ketoconazole orally 200mg three times daily as LDK with prednisone 5mg twice a day was performed for these patients. PSA doubling time (PSADT) was applied, which was defined as PSA increase status before LDK therapy. The equation was PSADT= log(2)×ΔT/[log(PSAbaseline)-log(PSAfailue)], in which PSAbaseline indicated baseline PSA and PSAfailue was the first value of previous treatment failure, ΔT was the time interval between them. As response criteria of effective treatment, PSA response rate was defined as the percentage of patients with PSA decline>=50 compared PSAbaseline. Continuous variables were categorized in analysis by optimal cutoff which provided the greatest prognostic value by P value-based approach. A multivariate model was used to develop a nomogram predicting PSA response. RESULTS 22 (31.0%) patients were evaluable as PSA responders. Table 1 indicated baseline testosterone and PSADT as sensitivity predictors for LDK effective treatment in logistic regression models. PSA response rate was 55.6%(20/36) and 5.7%(2/35) for patients with baseline testosterone>=0.1ng/mL and <0.1ng/mL and was 44.8%(13/29) and 21.4%(9/42) for patients with PSADT>=2.0 month and <2.0 month. The area under the curve (AUC) of receiver operating characteristic for then were 0.791(95% confidence interval[CI] 0.682-0.900) and 0.632(95% CI 0.490-0.774). Figure 1 showed the result of nomogram. CONCLUSIONS The baseline testosterone>=0.1ng/mL and PSADT>=2.0 month may be new predictors for better outcome of LDK therapy for CRPC. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e356-e357 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Guo-Wen Lin Shanghai, China, People's Republic of More articles by this author Xu-Dong Yao Shanghai, China, People's Republic of More articles by this author Ding-Wei Ye Shanghai, China, People's Republic of More articles by this author Bo Dai Shanghai, China, People's Republic of More articles by this author Yao Zhu Shanghai, China, People's Republic of More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...