3-month Prostate-specific Antigen Research Articles

Abstract 5651: Personalized transcriptomic profiling for advanced prostate cancer: Guiding second-generation hormonal drug selection

Abstract Introduction: Second-generation hormonal drugs have demonstrated significant efficacy in extending the survival of patients with advanced prostate cancer. These drugs operate through two distinct molecular mechanisms: inhibition of androgen biosynthesis and blockade of the androgen receptor. However, due to concerns of side effects, concurrent usage of multiple drugs is not recommended. A notable challenge is the eventual development of drug resistance, rendering all second-generation hormonal therapies ineffective. Currently, there is a lack of guidelines for helping patients choose the most suitable drug. In the context of pharmacogenomics, genetic differences can influence drug susceptibility and efficacy, with variations in genomic sequences and regulatory mechanisms impacting drug response at the transcriptional and translational levels. Considered the rapid processing capabilities of Affymetrix transcriptomic microarrays, we hypothesized that distinct gene signatures in patients who respond well or poorly to second-generation hormonal drugs could be identified and could act as a companion diagnostic tool. Methods: We enrolled 180 advanced prostate cancer patients, who fulfilled Taiwan national health insurance criteria of using second-generation hormonal drugs, from seven medical centers or regional hospitals in Taiwan at 3 time points: prior to drug administration, 3 months after treatment started and drug resistance developed. The RNA expression data and clinical parameters were analyzed, and classification models were built using IPA and R. Good or poor responders were defined by 3-month prostate-specific antigen (PSA) lowered by 90 percent. Results:: Differential expression and enrichment analyses post-treatment highlighted the activation of NF-kappa B signaling and various immune cell pathways. Notably, pathways related to primary immunodeficiency and IL-17 became prominent following the development of drug resistance. At the initial stages, distinct alterations in cell cycle pathways, particularly G1/S and G2/M, were observed between good and poor responders. This was elucidated through principal component analysis and subsequent dbscan clustering. To further distinguish between these responder groups, we utilized an integrative approach for feature selection, combining support vector machine, random forest classifier, and lasso regression. Despite the innovative approach, the model's error rate stood at approximately 15%, attributed mainly to the limited number of cases. Conclusion: Our study highlights the potential of using transcriptomic analysis to predict responses to second-generation hormonal drugs in advanced prostate cancer, paving the way for personalized treatment strategies. However, the need for larger cohort studies is evident to refine these predictive models and enhance their accuracy. Citation Format: Li-Hsin Chang, Hao-Han Chang, Xin-Yi Lin, Shu-Chi Wang, Chih-Pin Chuu, Deng-Neng Chen, Shu-Pin Huang, Chia-Yang Li. Personalized transcriptomic profiling for advanced prostate cancer: Guiding second-generation hormonal drug selection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5651.

Darolutamide plus androgen-deprivation therapy (ADT) versus ADT in metastatic hormone-sensitive prostate cancer: Open-label single-arm study with an external control arm (ARASEC).

TPS297 Background: Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor. In the phase 3 ARAMIS study (NCT02200614) in nonmetastatic castration-resistant prostate cancer (CRPC), DARO + ADT significantly improved metastasis-free survival and overall survival (OS) vs placebo + ADT, with a favorable tolerability and safety profile. In the phase 3 ARASENS study (NCT02799602) in metastatic hormone-sensitive prostate cancer (mHSPC), DARO + ADT + docetaxel significantly reduced the risk of death by 32.5% vs ADT + docetaxel (hazard ratio 0.68; 95% confidence interval 0.57–0.80; P<0.0001), with no additional adverse events. DARO + ADT vs ADT alone in patients (pts) with mHSPC is being evaluated in the ongoing, global (ex-US), phase 3 ARANOTE study (NCT04736199). The phase 2 ARASEC study (NCT05059236) will complement ARANOTE by evaluating DARO + ADT in US pts with mHSPC. Given that ADT alone is no longer an acceptable comparator in the US, an external control arm will be derived from a historical study. Methods: To participate in ARASEC, pts must have confirmed adenocarcinoma of the prostate, metastatic disease on conventional imaging for which they have not received prior systemic therapy, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2. Pts will receive DARO 600 mg twice daily + ADT (luteinizing hormone-releasing hormone agonist/antagonist or orchiectomy). ADT can be started ≤4 months before DARO, and there must be no evidence of progression on ADT before DARO initiation. The external control arm will be derived from 394 pts with mHSPC treated with ADT alone in CHAARTED (NCT00309985). Pts in the active and control arms will be matched 1:1 on baseline characteristics such as age, ECOG PS, CHAARTED-defined extent of disease, prior therapy, and Gleason score. The propensity score (ie, the assessed probability that a pt is allocated to the DARO + ADT arm based on baseline profile) will be used to address bias in estimating differential effects, by matching pts with scores within a narrow window across the cohorts. The primary endpoint is progression-free survival (PFS), defined as the time from enrollment to prostate-specific antigen (PSA) progression, radiologic or symptomatic progression, clinical deterioration, or death, whichever occurs first, as defined in CHAARTED. Secondary endpoints are OS, radiographic PFS, time to CRPC, 6-month PSA response (<0.2 ng/mL), and safety. The study will continue until either the event count threshold triggering the primary endpoint analysis (161 PFS events) has been met or all pts have been followed for ≥2 years after enrollment, whichever occurs later. ARASEC is enrolling, with the first pt enrolled in November 2021. As of September 10, 2022, 59 pts have been enrolled. The target total enrollment is 200 pts at 30 sites. Clinical trial information: NCT05059236 .

A Retrospective Study of the Effect of Metformin on Patients with Metastatic Prostate Cancer.

Previous studies demonstrated that metformin could lead to an inhibition of proliferation of cancer cells through a shift from anabolic to catabolic metabolism. In this study, we seek to investigate the effect of metformin in metastatic prostate cancer. Patients followed at Northwell Health Zuckerberg Cancer Center during 2014-2018 were included if they were diagnosed with metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (mCRPC), with ⩾6 months follow-up with and without metformin treatment. The primary outcomes, 6-month prostate-specific antigen (PSA) response, overall survival (OS), and radiographic progression free survival (rPFS), were evaluated. There were 267 patients included in the final analysis; 196 patients had mHSPC (73.2%) and 71 had mCRPC (26.8%). Within the mHSPC subjects, there was a significant difference in OS between metformin vs nonmetformin groups (148.5 vs 85.6 months; P < .046) in a univariate analysis; patients who took metformin had a significantly longer OS than subjects who did not (median OS: 148.5 vs 86 months; P < .046). There was no significant difference between the 2 groups with respect to either PSA response rate at 6 months or rPFS or OS in patients with mHSPC in both univariate and multivariate analysis. Within the mCRPC subjects, there was no significant difference between metformin and nonmetformin groups with respect to OS (43.3 vs 51.5 months; P < 0.160) or PSA response at 6 months (38.5% vs 57.1%; p < 0.24); however, patients on metformin had a significantly shorter rPFS in both the univariate analysis (7.3 vs 17.4; P < .0002) and in the multivariate analysis (HR = 2.52; 95% CI: 1.24m 5.11; P < .0109). Among patients with mHSPC, use of metformin was not significantly associated with improved OS in the multivariate analysis.

Correlation Between Trough Level of Abiraterone and Prostate-Specific Antigen (PSA) Response in Metastatic Hormone-Sensitive Prostate Cancer.

BackgroundProstate cancer growth is primarily driven by testosterone and 5α-dihydrotestosterone. Abiraterone is an irreversible inhibitor of CYP17, and CYP17 inhibition is a required step in testosterone biosynthesis. Previous studies have shown that abiraterone trough levels are predictive of prostate-specific antigen (PSA) response in metastatic castrate-resistant prostate cancer (mCRPC). It has not been demonstrated if this association exists for patients with metastatic hormone-sensitive prostate cancer (mHSPC). In this study, we aimed to explore the correlation and association between abiraterone trough levels and PSA levels in patients with mHSPC.Material/MethodsThis was a single-center, prospective, observational study of patients with mHSPC being treated with abiraterone acetate (AA) 1000 mg once daily. Abiraterone trough levels (22–26 h after drug administration) were drawn at 1, 3, and 7 months after treatment initiation.ResultsThirteen patients with mHSPC were enrolled, and complete pharmacokinetic data were available for 8 patients. The mean trough levels at 1 month, 3 months, and 7 months were 34.49 ng/mL (3.36–240.46), 13.82 ng/mL (2.91–29.96), and 15.7 ng/mL (3.58–26.86), respectively. The correlation between the 1-month abiraterone trough level and 1-month PSA level was 0.29 (P=0.38), between 3-month abiraterone trough and 3-month PSA was −0.61 (P=0.08), and between 7-month abiraterone trough and 7-month PSA was −0.31 (P=0.54).ConclusionsThis study demonstrated a trend toward a negative correlation between 3-month abiraterone trough levels and PSA levels, but the correlation was not statistically significant. A study with a larger prospective sample size is needed to validate these findings.

Three-month Prostate-specific Antigen Level After Androgen Deprivation Therapy Predicts Survival in Patients With Metastatic Castration-sensitive Prostate Cancer.

Although upfront combination therapies with androgen deprivation are recommended for patients with castration-sensitive prostate cancer (CSPC), combination therapies may be excessive for some patients. The aim of this study was to identify patients with favorable outcome under androgen deprivation therapy (ADT) alone. This study consisted of 242 patients with CSPC who received ADT alone. The association between 3-month prostate-specific antigen (PSA) value after ADT and survival was analyzed. The median overall survival for men with high-volume and/or high-risk cancer and those with low-volume low-risk cancer were 48.0 months and 103.0 months, respectively (p≤0.0001). Notably, in patients with low-volume low-risk cancer, the median overall survival for patients who achieved PSA ≤2 ng/ml at 3 months after ADT initiation was quite long at 112.0 months. Conventional ADT may be sufficient and upfront combination therapy may be excessive for those patients with favorable outcome.

Three-month posttreatment prostate-specific antigen level as a biomarker of treatment response in patients with intermediate-risk or high-risk prostate cancer treated with androgen deprivation therapy and radiotherapy.

Prostate-specific antigen (PSA) measurement after definitive radiotherapy (RT) and androgen deprivation therapy for localized prostate cancer has been proposed as an early prognostic biomarker. In the current study, the authors investigated the association between 3-month post-RT PSA level and biochemical progression-free survival (bPFS), prostate cancer-specific survival (PCSS), and overall survival (OS). A total of 5783 patients with intermediate-risk or high-risk localized prostate cancer who were diagnosed between 2000 and 2015 and treated with RT and androgen deprivation therapy were identified from Veterans Affairs data. Patients were divided into groups based on 3-month post-RT PSA values: <0.10 ng/mL, 0.10 to 0.49 ng/mL, and ≥0.50 ng/mL. The effect of the 3-month PSA group on bPFS, PCSS, and OS was evaluated in multivariable Cox models adjusting for potential confounders. There were 2651 patients with intermediate-risk and 3132 with high-risk disease; approximately 11% had a 3-month PSA level of ≥0.50 ng/mL. A higher 3-month PSA level was found to be strongly associated with each outcome; compared with patients in the group with a 3-month PSA value <0.10 ng/mL, the authors noted greater hazards for the patients with a 3-month PSA value ≥0.50 ng/mL (hazard ratio for bPFS: 5.23; PCSS: 3.97; and OS: 1.50 [P<.001 for all]) and the patients with a 3-month PSA value of 0.10 to 0.49 ng/mL (hazard ratio for bPFS: 2.41 [P<.001]; PCSS: 2.29 [P<.001]; and OS: 1.21 [P = .003]). When analyzed separately, the 3-month PSA level was found to be predictive of OS in the high-risk group (P<.001) but not the intermediate-risk group (P = .21). The 3-month post-RT PSA level appears to be a strong prognostic biomarker for bPFS, PCSS, and OS in patients with intermediate-risk and high-risk prostate cancer, particularly those with high-risk disease. The 3-month PSA measurement may augment clinical decision making and holds promise as a potential surrogate endpoint in clinical trials. Cancer 2018;124:2939-47. © 2018 American Cancer Society.

Three-month post-treatment PSA as a biomarker of treatment response in intermediate or high-risk prostate cancer treated with androgen deprivation therapy and radiotherapy.

99 Background: Prostate-specific antigen (PSA) measurement after definitive radiation therapy (RT) and androgen deprivation therapy (ADT) for localized prostate cancer (PC) has been proposed as an early prognostic biomarker. We investigate the association between 3-month post-RT PSA and biochemical progression-free survival (bPFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Methods: We identified 5,783 patients with intermediate- or high-risk localized PC diagnosed between 2000-2015 and treated with RT and ADT from Veterans Affairs data. Patients were divided into groups based on 3-month post-RT PSA values: &lt; 0.10 ng/mL, 0.10-0.49 ng/mL, and ≥0.50 ng/mL. The effect of 3-month PSA group on bPFS, PCSS, and OS were evaluated in multivariable Cox models adjusting for potential confounders. Results: There were 2,651 intermediate risk and 3,132 high risk patients; 11% had a 3-month PSA of ≥0.50 ng/mL. Higher 3-month PSA was strongly associated with each outcome; compared to the &lt; 0.10 ng/mL group, we noted greater hazards for the 0.10-0.49 ng/mL group (HR for bPFS: 2.41, p &lt; 0.001; PCSS: 2.29, p &lt; 0.001; OS: 1.21, p = 0.003) and the ≥ 0.50 ng/mL group (HR for bPFS: 5.23; PCSS: 3.97; OS: 1.50; p &lt; 0.001 for all). When analyzed separately, 3-month PSA group was predictive of OS in the high-risk group (p &lt; 0.001) but not the intermediate-risk group (p = 0.21). Conclusions: 3-month post-RT PSA is a strong prognostic biomarker for bPFS and PCSS in patients with intermediate and high-risk PC, and OS in patients with high-risk PC. 3-month PSA measurement may augment clinical decision-making and holds promise as a potential surrogate endpoint in clinical trials.

Testosterone nadir and PSA recurrence-free survival in men with intermediate and high-risk localized prostate cancer undergoing definitive radiotherapy and androgen deprivation therapy.

100 Background: There is limited data on the relationship between testosterone level during androgen deprivation and clinical outcomes of localized prostate cancer treated with hormone therapy and radiation therapy (RT). Here we investigate the association between testosterone nadir during androgen deprivation therapy and prostate-specific antigen (PSA) response and survival. Methods: Using a nationwide Veterans Affairs database, we identified 899 patients with intermediate- or high-risk localized prostate adenocarcinoma diagnosed between 2000 and 2015 and treated with gonadotropin-releasing hormone agonists and RT. All patients had total testosterone measurements while receiving hormone therapy and between 6 weeks and 6 months after the start of hormone therapy. Using univariable and multivariable models we examined the effect of testosterone nadir on 3-month post-treatment PSA, PSA recurrence-free survival, and prostate cancer-specific survival. Multivariable models included age at diagnosis, Gleason score, tumor stage, anti-androgen therapy, hormone therapy duration, comorbidity, BMI, and pre-treatment PSA. Results: Of the 899 patients with testosterone data, 481 patients had a testosterone nadir of &lt; 20 ng/dL, 305 had a nadir between 20 and 49 ng/dL, and 113 had a nadir ≥50 ng/dL. Higher testosterone nadir was associated with higher 3-month post-treatment PSA on univariable (Spearman rho = 0.22, p &lt; 0.001, n = 651) and multivariable (ß = 0.03, 95% CI 0.01-0.05, p = 0.004) analysis. In multivariable Cox regression, higher testosterone nadir was associated with an increased risk of PSA recurrence (hazard ratio [HR] 1.43 per 10-fold increase in testosterone nadir, 95% CI 1.07-1.90, p = 0.01, n = 715) but not prostate cancer-specific mortality (HR 1.45, 95% CI 0.87-2.42, p = 0.16, n = 891). Conclusions: Higher nadir testosterone levels in intermediate- or high-risk localized prostate cancer patients undergoing hormone therapy is associated with higher 3-month post-treatment PSA and inferior PSA recurrence-free survival, though there was no significant effect on prostate cancer-specific mortality.

Relation between plasma trough concentration of abiraterone and prostate-specific antigen response in metastatic castration-resistant prostate cancer patients

BackgroundAbiraterone (ABI) is a major oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients but its systemic exposure is subject to a large inter-individual variability. We aimed to explore the relationship between ABI trough plasma concentration and prostate-specific antigen (PSA) response in mCRPC patients and to identify the critical determinants for its activity. Patients and methodsThis is a monocentric prospective observational study in mCRPC patients treated with ABI. The plasmatic concentration of ABI at steady state was measured using liquid chromatography with fluorescence detection. The primary objective was to study the relationship between mean ABI plasma exposure (ABI Cmin) and 3-month PSA response. ResultsFrom 2012 to 2016, 61 mCRPC patients were eligible for pharmacokinetic/pharmacodynamic assessment. Thirty-eight patients experienced PSA response (62%, [confidence interval {CI} 95% 50–78]). In univariate analysis, ABI Cmin was 1.5-fold higher in responders: 12.0 ng/mL (CI 95% 9.4–15.6) versus 8.0 ng/mL (CI 95% 5.8–11.6; P = 0.0015). In multivariate analysis, only ABI Cmin was independently associated with PSA response (odds ratio = 1.12 [CI 95% 1.01–1.25], P = 0.004). By receiver operating characteristic analysis, the optimal threshold for ABI Cmin was 8.4 ng/mL. Progression-free survival (PFS) was significantly higher in patients with ABI Cmin above 8.4 ng/mL (hazard ratio 0.55, [CI 95% 0.31–0.99], 12.2 [CI 95% 9.2–19.5] versus 7.4 [CI 95% 5.5–14.7] months otherwise, P = 0.044). ConclusionsWe showed that ABI trough concentration correlates with PSA response and PFS. Moreover, we could determine a cut-off value of plasmatic concentration for PSA response. Altogether, ABI concentration monitoring appears as a new approach to improve clinical outcome in mCPRC patients.

Prostate-specific antigen vs. magnetic resonance imaging parameters for assessing oncological outcomes after high intensity–focused ultrasound focal therapy for localized prostate cancer

IntroductionFocal therapy for localized prostate cancer has the potential for oncological control without the side effects of radical therapies. However, there is currently no validated method for monitoring treatment success. We assessed the diagnostic performance of prostate-specific antigen (PSA) parameters and MRI compared to histological outcomes following focal therapy. Patients and methodsPatients from 3 Ethics Review Board approved prospective studies of focal high intensity–focused ultrasound (HIFU) (Sonablate 500) for localized prostate cancer (T1c–T3a, Gleason grade≤4+3, and PSA≤20). Post-HIFU PSA nadir, 6-month PSA, PSA density, and early (<3wk) and late (6mo) MRI (T2-weighted, dynamic contrast-enhanced±diffusion-weighted) was assessed for predictive accuracy of cancer on postoperative biopsy, using receiver operating characteristic (ROC) analysis and sensitivity, specificity, and positive and negative predictive estimates. ROC areas for MRI and PSA were compared. Calculations for statistical significance (P≤0.05) were obtained in a subset of patients comparing area under ROC for 6-month MRI and PSA criteria, across 4 different histological definitions of disease significance. ResultsOf 118 men, 111 underwent at least 1 postoperative biopsy (median 6 cores), with an overall positive biopsy rate of 37% (41/118), over a mean follow-up period of 716 days post-HIFU. Areas under ROC for early and late MRI were (depending on definition of significant disease) 0.65 to 0.76 and 0.77 to 0.85, respectively, with sensitivity, specificity, and negative predictive values of 68% to 91%, 52% to 55%, and 85% to 98% (early MRI), and 63% to 80%, 67% to 73%, and 86% to 97% (late MRI). The area under the ROC curve was statistically significantly higher for late MRI than 6 months and nadir PSA for residual disease >3mm or any Gleason 4 tumor. ConclusionsEarly and late MRI performed better than PSA measurements in the detection of residual tumor after focal therapy.

Distinguishing prostate-specific antigen bounces from biochemical failure after low-dose-rate prostate brachytherapy.

PurposeThe purpose of this study was to characterize benign prostate-specific antigen (PSA) bounces of at least 2.0 ng/mL and biochemical failure as defined by the Phoenix definition after prostate brachytherapy at our institution, and to investigate distinguishing features between three outcome groups: patients experiencing a benign PSA bounce, biochemical failure, or neither.Material and methodsFive hundred and thirty consecutive men treated with low-dose-rate brachytherapy with follow-up of at least 3 years were divided into outcome groups experiencing bounce, failure, or neither. A benign bounce was defined as a rise of at least 2.0 ng/mL over the pre-rise nadir followed by a decline to 0.5 ng/mL or below, without intervention. Patient and tumor characteristics, treatment variables, and PSA kinetics were analyzed between groups.ResultsThirty-two (6.0%) men experienced benign bounces and 47 (8.9%) men experienced failure. Men experiencing a bounce were younger (p = 0.01), had a higher 6-month PSA level (p = 0.03), and took longer to reach a final nadir (p < 0.01). Compared to the failure group, men with bounce had a lower pre-treatment PSA level (p = 0.01) and experienced a rise of at least 2.0 ng/mL that occurred sooner after the implant (p < 0.01) with a faster PSA doubling time (p = 0.01). Only time to PSA rise independently differentiated between bounce and failure (p < 0.01), with a benign bounce not being seen after 36 months post-treatment. Prostate-specific antigen levels during a bounce reached levels as high as 12.6 ng/mL in this cohort, and in some cases took over 5 years to decline to below 0.5 ng/mL.ConclusionsAlthough there is substantial overlap between the features of benign PSA bounces and failure, physicians may find it useful to evaluate the timing, absolute PSA level, initial response to treatment, and rate of rise when contemplating management for a PSA rise after low-dose-rate brachytherapy.

The impact of reducing the frequency of prostate specific antigen (PSA) testing among men on active surveillance for prostate cancer.

5092 Background: Active surveillance is a management strategy for men with low risk prostate cancer. Most surveillance regimens include routine PSA assessments, typically performed q 3 mos, although recent studies have questioned the utility of short-term PSA kinetics. Moreover, frequent PSA assessments may be associated with repeated intervals of anxiety around the time of testing, decreasing overall quality of life and potentially leading to avoidable interventions. We hypothesized that PSA assessment q 6 mos rather than q 3 mos would yield similar PSA kinetics calculations. Methods: We analyzed data from the Prostate Active Surveillance Study (PASS), a prospective, multicenter cohort accruing data and biospecimens from men on surveillance at 9 sites across North America. In PASS, PSAs are measured q 3 mos, with high completeness of data. We included data from men who had at least 5 PSA assessments after diagnosis, separated by ≥6 months (most had 10 PSAs separated by 3 months). PSA doubling time (PSADT) was calculated as ln(2) divided by the slope of a regression line drawn through the 5 PSAs. PSADT3 and PSADT6 were defined as the PSADT calculated from q 3 mos and q 6 mos data, respectively; for PSADT6, PSAs between each 6-month measurement were ignored. In each case, PSADT of 0-3 years defined progression, and PSADT &gt; 3 years or declining PSA defined non-progression. Results: 161 men had sufficient PSA followup for analysis. 133 had no progression by either PSADT3 or PSADT6, and 16 progressed by both PSADT calculations. 4 and 8 men, respectively, progressed only by the PSADT3 or PSADT6 calculation but not by the other calculation. The κ score for agreement of progression ascertainment between PSADT3 and PSADT6 was 0.68, and McNemar’s test indicated no statistically significant difference between the two assessments (p=0.39). Conclusions: Calculating PSADT using 6-month rather than 3-month PSA assessments does not significantly change ascertainment of PSA progression in men on surveillance. Our finding suggests that surveillance protocols may reduce the frequency of PSA testing, potentially reducing unnecessary biopsy procedures and patient anxiety due to more frequent PSA measurements.

Safety, pharmacokinetics, and efficacy of TAK-700 in metastatic castration-resistant prostrate cancer: A phase I/II, open-label study.

3084 Background: TAK-700 is a selective 17,20 lyase inhibitor that substantially reduced in vivo adrenal androgen levels in preclinical studies. Methods: This phase I/II open-label, dose-escalation study assesses the safety and tolerability of oral twice-daily (BID) TAK-700 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Secondary objectives include assessment of efficacy, as shown by prostate-specific antigen (PSA) response, and TAK-700 pharmacokinetics (PK). Here we report the phase I portion of the study. Results: 26 pts (median age 70 y, 11 had received prior ketoconazole) received TAK-700 at 5 dose levels: 100 (3 pts), 200 (3), 300 (3), 400 (6) or 600 (5) mg BID; a further 6 pts received TAK-700 400 mg BID plus prednisone 5 mg BID. At data cut-off (29 Dec 2009), 11 pts remain on study; 15 patients discontinued, including 6 due to adverse events (AEs), 4 due to radiologic disease progression, 2 due to PSA progression, 2 due to patient request and 1 for other reasons. All pts experienced ≥1 treatment-emergent AE (TEAE); 92% were drug-related and 54% were grade ≥3. The most common TEAE was fatigue (17 pts, 3 grade ≥3 with 600 mg BID), followed by non-dose-related GI events such as nausea (11 pts, 1 grade 3), constipation (10), anorexia (9) and vomiting (7, 2 grade ≥3). Preliminary PK analysis indicates approximate dose- proportional increases in single- and multiple-dose Cmax and AUC0–8hr over the 100–600 mg BID dose range. Multiple-dose PK are consistent with the single-dose PK. At 4 wks, median testosterone and DHEA-S levels had decreased from 5.5 to 0.6 ng/dL and 50.0 μ g/dL to below quantifiable levels, respectively, in all patients treated with TAK-700. All patients treated with ≥300 mg had a PSA decrease; of 15 pts who received TAK-700 ≥300 mg for ≥3 cycles and had a 3-month PSA determination, 12 (80%) had PSA reductions ≥50% and 4 (27%) had reductions ≥90%. Conclusions: TAK-700 ≥300 mg BID appears active and well tolerated in pts with mCRPC. The phase II portion of the study is ongoing (31 pts enrolled by data cut-off) and will further assess the safety and efficacy of TAK-700 and the need for concomitant prednisone. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium AstraZeneca, Endo Pharmaceuticals, MethylGene, Millennium, Ortho Biotech, Transgene sanofi-aventis Millennium

Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone‐releasing hormone therapy: prognostic significance?

To determine if the testosterone level achieved with androgen-deprivation therapy (ADT) is directly related to survival and risk of death in men with metastatic prostate cancer, as agonistic analogues of luteinizing hormone-releasing hormones (LHRH) are indicated for palliative treatment of these patients, but there is no consensus about the utility of serum testosterone measurements during the follow-up, and their possible prognostic value. We retrospectively reviewed 129 consecutive patients with a histological diagnosis of metastatic bony-only prostate cancer and previously untreated with ADT. They were treated with 3 months of goserelin. Testosterone and prostate-specific antigen (PSA) levels were measured in all patients every 3 months for the duration of the follow-up. The following variables were recorded: age, stage, Gleason score, basal PSA level, basal testosterone level, PSA nadir, time to PSA nadir, testosterone after 6 months, testosterone nadir and time to testosterone nadir. Data were analysed using Cox's proportional hazards models, with the primary endpoint being cancer-specific survival. The mean (SD) basal PSA level was 185.8 (344.1) ng/mL, and the mean nadir PSA level 2.7 (8.6) ng/mL. The mean testosterone levels at baseline, 6 months and the nadir were 440 (200), 40 (40) and 21 (15) ng/dL. With a mean follow-up of 47.5 (29.7) months, 71 patients were dead (55%) and 78 were alive (45%) at the time of analysis. Statistical analysis using Cox's model showed that in these patients the risk of death was directly correlated not only to Gleason score (P < 0.01) and to the 6-month PSA level (P < 0.01), but also to the 6-month serum testosterone level (hazard ratio 1.32, P < 0.05). These results suggest a direct correlation between the risk of death and testosterone levels achieved during ADT. Based on the present results, lowering the testosterone level as much as possible should be the goal of ADT in patients with metastatic prostate cancer, as this might affect patient survival.

Addition of DMXAA (ASA404) to docetaxel in patients with hormone-refractory metastatic prostate cancer (HRMPC): update from a randomized, phase II study

5007 Background: DMXAA (ASA404) is a novel tumor vascular disrupting agent. In animal models DMXAA has synergistic anti-tumor effects in combination with cytotoxics, including taxanes. A randomized study in non-small cell lung cancer reported a 5-month survival benefit when DMXAA was added to carboplatin+paclitaxel. This randomized phase II study examined the efficacy and safety of DMXAA in combination with docetaxel in HRMPC. We reported previously that the DMXAA-docetaxel combination was well-tolerated and increased PSA response rate compared with docetaxel alone (59 vs 37%). Data are now available on 3-month PSA reduction, tumor response rates and time to tumor progression (TTP). Methods: Patients had progressive metastatic, androgen-independent, histologically confirmed prostate adenocarcinoma, previously untreated with cytotoxics. Patients were randomized to receive docetaxel (75 mg/m2) ± DMXAA (1200 mg/m2) every 21 days for up to 10 cycles. Efficacy endpoints included prostate-specific antigen (PSA) response rate, objective response rate, time to tumor progression and median survival. Results: 33 patients received DMXAA plus docetaxel (DMXAA arm). 38 patients received docetaxel alone (control arm). Similar numbers of patients in each arm experienced serious adverse events (14 vs 13 in the DMXAA and control arms, respectively). 62.5% patients in the DMXAA arm had at least a 30% reduction in PSA during the first 3 months, compared with 47.4% patients in the control arm. Response rates by modified RECIST were 23.1% and 9.1% in the DMXAA and control arms (among 26 and 33 assessable patients), respectively. Investigator-determined time to tumor progression was 7.3 months in the DMXAA arm and 6.9 months in the control arm. Conclusions: Addition of DMXAA to a standard docetaxel regimen was generally well tolerated. Data on 3-month PSA reduction, tumor response rate and TTP support previous PSA response findings in suggesting improved efficacy with a DMXAA-docetaxel combination compared to docetaxel alone. Further evaluation of DMXAA in HRMPC is warranted. No significant financial relationships to disclose.

Prostate-Specific Antigen and Pain Surrogacy Analysis in Metastatic Hormone-Refractory Prostate Cancer

It is currently unclear if early prostate-specific antigen (PSA) or pain improvements are adequate surrogates for overall survival in men with metastatic hormone-refractory prostate cancer (HRPC). Here we examined various degrees of PSA decline and pain response as surrogates for the survival benefit observed in the TAX327 trial. In the TAX327 trial, 1,006 men with HRPC were randomly assigned to receive docetaxel in two schedules, or mitoxantrone, each with prednisone: 989 men provided data on 3-month PSA decline. Surrogacy was examined for post-treatment changes in PSA and pain response using Cox proportional hazards models to calculate the proportion of treatment effect (PTE) explained by each potential surrogate. A > or = 30% PSA decline within 3 months of treatment initiation provides the highest degree of surrogacy, with a PTE of 0.66 (95% CI, 0.23 to 1.0), and was associated with a hazard ratio (HR) of 0.50 (95% CI, 0.43 to 0.58) for overall survival after adjusting for treatment effect. Introduction of a > or = 30% PSA decline is predictive of survival regardless of treatment arm. Other changes in PSA or PSA kinetics, PSA normalization, and pain responses were highly prognostic but weaker surrogates for survival. In the TAX327 trial, a PSA decline of > or = 30% within 3 months of chemotherapy initiation had the highest degree of surrogacy for overall survival, confirming data from the Southwest Oncology Group 9916 trial. However, given the wide CIs around the estimate of this moderate surrogate effect, overall survival should remain the preferred end point for phase III trials of cytotoxic agents in HRPC.

Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16: Petrylak DP, Ankerst DP, Jiang CS, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED, Columbia University, New York, NY

Background The identification of surrogate endpoints that can replace true outcome endpoints is crucial to the rapid evaluation of new cancer drugs. Retrospective analyses of phase II and III trials in metastatic androgen-independent prostate cancer have shown associations between declines in serum prostate-specific antigen (PSA) levels and survival. We evaluated PSA changes as potential surrogate markers for survival by using data from a clinical trial. Methods Men with androgen-independent prostate cancer were randomly assigned to either docetaxel/estramustine (D/E) or mitoxantrone/prednisone (M/P) treatment on Southwest Oncology Group Protocol 99-16. Of 674 eligible patients, 551 had a baseline PSA measurement and at least one PSA measurement during the first 3 months on protocol. PSA level declines of 5%–90% and PSA velocity at 1, 2, and 3 months were tested for surrogacy by using three statistical criteria: Prentice’s criteria, the proportion of treatment effect explained, and the proportion of variation explained. All statistical tests were two-sided. Results Three-month PSA level declines of 20%–40%, a 2-month PSA decline of 30%, and PSA velocity at 2 and 3 months met all three surrogacy criteria. For example, a 3-month PSA decline of at least 30% was associated with a more than 50% decrease in the risk of death compared with the lack of such a decline (hazard ratio [HR] = 0.43, 95% confidence interval [CI] = 0.34 to 0.55; P P = .032) lost statistical significance after adjustment for this surrogate, whereas the decrease in risk of death associated with a 3-month 30% PSA decline remained statistically significant after adjustment for treatment. PSA level declines of 50%, commonly reported in clinical trials, did not meet the criteria for surrogacy. Conclusions Several PSA measures satisfied the surrogacy criteria for survival in a retrospective analysis of data from SWOG 99-16. However, these measures await prospective validation in future clinical trials of chemotherapy in men with androgen-independent prostate cancer.

Evaluation of Prostate-Specific Antigen Declines for Surrogacy in Patients Treated on SWOG 99-16

The identification of surrogate endpoints that can replace true outcome endpoints is crucial to the rapid evaluation of new cancer drugs. Retrospective analyses of phase II and III trials in metastatic androgen-independent prostate cancer have shown associations between declines in serum prostate-specific antigen (PSA) levels and survival. We evaluated PSA changes as potential surrogate markers for survival by using data from a clinical trial. Men with androgen-independent prostate cancer were randomly assigned to either docetaxel/estramustine (D/E) or mitoxantrone/prednisone (M/P) treatment on Southwest Oncology Group Protocol 99-16. Of 674 eligible patients, 551 had a baseline PSA measurement and at least one PSA measurement during the first 3 months on protocol. PSA level declines of 5%-90% and PSA velocity at 1, 2, and 3 months were tested for surrogacy by using three statistical criteria: Prentice's criteria, the proportion of treatment effect explained, and the proportion of variation explained. All statistical tests were two-sided. Three-month PSA level declines of 20%-40%, a 2-month PSA decline of 30%, and PSA velocity at 2 and 3 months met all three surrogacy criteria. For example, a 3-month PSA decline of at least 30% was associated with a more than 50% decrease in the risk of death compared with the lack of such a decline (hazard ratio [HR] = 0.43, 95% confidence interval [CI] = 0.34 to 0.55; P < .001), and the increased risk of death for men treated with M/P compared with D/E (HR = 1.24, 95% CI = 1.02 to 1.51; P = .032) lost statistical significance after adjustment for this surrogate, whereas the decrease in risk of death associated with a 3-month 30% PSA decline remained statistically significant after adjustment for treatment. PSA level declines of 50%, commonly reported in clinical trials, did not meet the criteria for surrogacy. Several PSA measures satisfied the surrogacy criteria for survival in a retrospective analysis of data from SWOG 99-16. However, these measures await prospective validation in future clinical trials of chemotherapy in men with androgen-independent prostate cancer.

Prostate-specific antigen variability in men without prostate cancer: effect of sampling interval on prostate-specific antigen velocity

Objectives To evaluate short-term and long-term variability between prostate-specific antigen (PSA) measurements to determine the most appropriate PSA sampling interval and rate of PSA change (PSA velocity) to distinguish between men with and without prostate cancer. Methods Retrospective study of PSA variability and PSA velocity in three groups of men without a diagnosis of prostate cancer and PSA levels less than 10 ng/mL: 56 men with a histologic diagnosis of benign prostatic hyperplasia (BPH; histologic BPH group) and 527 men with no history of cancer (noncancer group) who were part of the Baltimore Longitudinal Study of Aging and had PSA sampled at 2-year intervals (long-term), and 223 men with a clinical diagnosis of BPH (clinical BPH group) who had PSA sampled at 3-month intervals (short-term). PSA variability (deviation between consecutive measurements) and PSA velocity based on both two consecutive measurements and three consecutive measurements (average velocity) were calculated for each study group. Results PSA velocity is the deviation in PSA measurements relative to the elapsed time between the measurements. Because the variability in PSA between measurements was similar for the groups, the major factors that influenced PSA velocity were the sampling interval between PSA measurements, and to a lesser extent, the number of repeat PSA measurements. The 99th percentile for PSA velocity was 0.7 (histologic BPH group) and 0.75 ng/mL per year for the noncancer group when three measurements with a 24-month PSA sampling interval were used. However, the 99th percentile for PSA velocity was 5.8 and 2.4 ng/mL per year when three measurements with 3-month and 6-month PSA sampling intervals were used. Using three measurements, the percentage of subjects with a PSA velocity more than 0.75 ng/mL per year was 1 % for the groups with a 24-month PSA sampling interval and 28% and 17% for 3-month and 6-month PSA sampling intervals, respectively. The 99th percentile for PSA velocity and the percentage of subjects with a PSA velocity more than 0.75 ng/mL per year was higher using two measurements compared to three measurements regardless of PSA sampling interval. Conclusions PSA velocity is inversely related to the interval between PSA measurements. A PSA velocity more than 0.75 ng/mL per year is useful in distinguishing between men with and without prostate cancer when: (1) velocity is based on three consecutive measurements; and (2) PSA is sampled long-term (2 years) but not short-term (3 to 6 months).

Prostate-specific antigen decline: a major prognostic factor for prostate cancer treated with radiation therapy.

To assess the prognostic significance of serum prostate-specific antigen (PSA) in the monitoring of patients with localized prostate cancer treated with primary radiation therapy, we analyzed the data from 179 patients treated at our institution between 1987 and 1990. One hundred seventy-nine previously untreated patients received radiation at 69 Gy to the prostate with curative intent for prostate adenocarcinoma. The median follow-up duration is now 41 months. PSA levels were measured before radiotherapy and then evaluated periodically. Baseline levels were greater than 4 ng/mL in 83% of cases and were significantly correlated with clinical tumor stage (P = .002). Six months after completion of therapy, PSA values had returned to normal in 53% of the patients with initially elevated values. At the time of analysis, 32 patients have relapsed, including three of 30 patients (10%) with normal initial and 6-month values, five of 79 patients (6%) with initially elevated but normal 6-month values, and 24 of 69 patients (35%) with persistently elevated PSA levels at 6 months. Actuarial 4-year relapse-free survival was significantly correlated with initial and 6-month PSA values (84% in patients with normal 6-month values v 60% in patients with persistently elevated levels). Furthermore, when the relative decline between initial and 6-month PSA values exceeded 50%, the crude rate of recurrence was 14% as opposed to 34% when it failed to exceed 50%. The 4-year relapse-free survival rates were 77% and 59%, respectively (P = .008). By multivariate analysis restricted to the patients with elevated baseline PSA levels, the rate of decline of PSA values reached the highest prognostic significance (P < .0001). Age at diagnosis, clinical tumor stage, and Gleason score only reached statistical significance in univariate analysis. PSA values are of major prognostic significance in assessing the 4-year results of radical radiation therapy for localized prostate cancer. The rate of decline of PSA values is the strongest predictor of outcome and might help to identify a subset of patients with poorer prognosis who may benefit from early hormonal therapy.