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Undetectable prostate-specific antigen after short-course androgen deprivation therapy for biochemically recurrent patients correlates with metastasis-free survival and prostate cancer-specific survival.

ABSTRACT: BACKGROUND:Optimal utilization of novel therapies for advanced prostate cancer is challenging without a validated surrogate efficacy endpoint. Ongoing trials are using durable undetectable prostate-specific antigen (PSA) levels as a marker of efficacy. The clinical relevance of prolonged undetectable PSA after a short course of androgen deprivation therapy (ADT) is uncertain. METHODS:The University of Washington Caisis database was queried for radical prostatectomy patients who received 6-12 months of ADT after biochemical recurrence (BCR), defined as PSA ?0.2?ng/mL and no radiographically detectable metastasis. Proportions of men with undetectable PSA 12 and 24 months after ending ADT were compared to a hypothesized 5% rate using exact binomial tests. Associations with patient and tumor characteristics were examined using logistic regression, and associations with risk of subsequent metastasis and death were evaluated by log-rank tests. RESULTS:After ineligibility exclusions, 23/93 (25%; 95%CI 16-35%; P?

SUBMITTER: Lim DM

PROVIDER: S-EPMC6328347 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Undetectable prostate-specific antigen after short-course androgen deprivation therapy for biochemically recurrent patients correlates with metastasis-free survival and prostate cancer-specific survival.

Lim Daniel M DM Gulati Roman R Aleshin-Guendel Serge S Gawne Agnes A Wingate Jonathan T JT Cheng Heather H HH Etzioni Ruth R Yu Evan Y EY

The Prostate 20180710

<h4>Background</h4>Optimal utilization of novel therapies for advanced prostate cancer is challenging without a validated surrogate efficacy endpoint. Ongoing trials are using durable undetectable prostate-specific antigen (PSA) levels as a marker of efficacy. The clinical relevance of prolonged undetectable PSA after a short course of androgen deprivation therapy (ADT) is uncertain.<h4>Methods</h4>The University of Washington Caisis database was queried for radical prostatectomy patients who re ...[more]

PMID: 29987912

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Project description:PurposeThis randomized phase 2 study sought to assess the treatment effect of a finite duration of apalutamide with and without androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BCR PC). Materials and Methods. Patients with BCR PC after primary definitive therapy and prostate-specific antigen (PSA) doubling time ≤12 months were randomized to open-label apalutamide (240 mg/d) alone, apalutamide plus ADT, or ADT alone (1 : 1:1 ratio) for 12 months followed by a 12-month observation period (NCT01790126). Mean changes from baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) at 12 months (primary endpoint) and other prespecified assessments of health-related quality of life (HRQoL), PSA nadir, time to PSA progression, time to testosterone recovery, recovered testosterone >150 ng/dL without PSA progression at 24 months, and molecular markers were evaluated.ResultsIn 90 enrolled patients (apalutamide plus ADT (n = 31), apalutamide (n = 29), ADT (n = 30)), FACT-P at 12 months was not significantly different between apalutamide, ADT and apalutamide, and ADT groups. Addition of apalutamide to ADT prolonged time to PSA progression but this change did not reach statistical significance (hazard ratio (HR): 0.56, 95% confidence interval (CI): 0.23-1.36, P=0.196); time to testosterone recovery was similar in the ADT-containing groups. In apalutamide plus ADT, apalutamide, and ADT groups, 37.9%, 37.0%, and 19.2% of patients, respectively, had testosterone >150 ng/dL at 24 months without confirmed PSA progression. Of the few biomarkers expressed in blood, EPHA3 was significantly associated with shorter time to PSA progression (P=0.02) in the overall population.ConclusionsHRQoL was similar in patients treated with apalutamide alone, ADT alone, or their combination, although apalutamide plus ADT did not demonstrate statistically significant noninferiority in change from baseline in overall HRQoL. The aggregated efficacy and safety outcomes support further evaluation of apalutamide plus ADT in BCR PC.

Project description:Based on in vitro studies, it is known that androgen deprivation therapy (ADT) increases prostate-specific membrane antigen (PSMA) expression on prostate cancer (PCa) cells. However, ADT also has cytoreductive effects which can decrease lesion size. The present evaluation was conducted to further analyze the influence of ongoing ADT on [18F]DCFPyL positron emission tomography/computed tomography (PET/CT) performance in the setting of biochemically recurrent PCa. We retrospectively evaluated two groups of PCa patients, previously treated with radical intent, who had undergone [18F]DCFPyL PET/CT because of biochemical relapse with a minimum PSA level of 0.4 ng/mL. One group consisted of 95 patients under ADT at the time of the PET examination, and the other consisted of 445 patients not receiving ADT at the time of PET/CT. The uptake characteristics of the cardiac blood pool, liver, parotid glands, and five most active lesions were measured and compared between these two groups. The overall detection rate of [18F]DCFPyL PET/CT in patients under ADT at the time of imaging was significantly higher than patients not under ADT (91.6% vs. 80.4%, p-value = 0.007). However, the PSA-stratified differences in detection rates between patients with and without ADT did not reach statistical significance. Except for the maximal standardized uptake values corrected for lean body mass (SULmax) in the PSA range of 1 to <2 ng/mL, the intensity and volume of [18F]DCFPyL accumulation were higher in patients with ADT compared to the patients without. Statistical significance was attained for the SULmax in PSA range of 0.5 to <1 ng/mL (p-value = 0.0004) and metabolic tumor volume (MTV) in all PSA ranges (p-values of 0.0005 to 0.03). No significant difference was observed for radiotracer uptake in normal organs between the two groups with and without ADT. In this study population with biochemical recurrence of PCa and measurable PSA, ongoing ADT at the time of [18F]DCFPyL PET/CT imaging was associated with higher radiotracer uptake and overall lesion detection rate. This could be due in part to the more aggressive disease phenotype in patients with ongoing ADT.

Project description:BackgroundNo standard of care exists for patients with high-risk biochemical recurrence (BCR) after prostatectomy.ObjectiveTo evaluate whether addition of docetaxel to androgen deprivation therapy (ADT) improved progression-free survival (PFS) in high-risk BCR patients.Design, setting, and participantsTAX3503 was a multicenter phase 3 trial that randomized patients with high-risk BCR to ADT for 18 mo ± docetaxel (75 mg/m2 q3w for ten cycles). Eligibility included prostate-specific antigen (PSA) ≥1.0 ng/ml after prostatectomy alone or after postoperative radiation therapy, PSA doubling time ≤9 mo, and absence of metastases on computed tomography and bone scintigraphy.Outcome measurements and statistical analysisThe primary endpoint was PFS following testosterone recovery to noncastrate levels (testosterone >50 ng/dl). Secondary endpoints included time to testosterone recovery, overall survival (OS), quality of life, and safety.Results and limitationsBetween September 2007 and May 2011, 413 patients were assigned to ADT ± docetaxel. In 2012, following completion of accrual and treatment, the sponsor withdrew support of the study, and in 2013, a registry was created to secure the primary endpoint. The final analysis included data from the original trial and registry. At a median follow-up of 33.6 mo, 260 patients demonstrated testosterone recovery, which occurred similarly between groups. ADT plus docetaxel trended toward a nonclinically meaningful improvement in PFS (median 26.2 vs 24.7 mo) for the testosterone-recovered population (218 events, hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.61-1.04) and in OS for the intention-to-treat population (medians not reached, HR 0.51, 95% CI 0.23-1.10). Grade ≥3 adverse events occurred more frequently in the ADT plus docetaxel group (48.0% vs 10.8%).ConclusionsTAX3503 did not demonstrate a meaningful benefit of adding docetaxel to ADT in patients with high-risk BCR. Testosterone recovery was unaffected by addition of docetaxel to ADT.Patient summaryAddition of docetaxel to androgen deprivation therapy did not meaningfully improve outcomes for men with high-risk biochemically recurrent prostate cancer.

Project description:IntroductionHigh folate has an association with advanced prostate cancer and levels of testosterone. Herein, we perform a translational study to investigate the inverse response of serum folate in prostate cancer patients initiating androgen deprivation therapy (ADT) and a mirrored animal model.MethodsA retrospective study was performed using the South Texas Veterans Healthcare System to identify patients with prostate cancer on ADT. We documented testosterone and folate levels before and after ADT initiation (defined by a reduction in testosterone by 50 ng/ml) as compared to those already on ADT (maintenance). Our primary outcome was overall mortality with secondary outcome of prostate cancer-specific mortality. In parallel, we tested castration of C57BL/6J mice on folate-defined diet to determine if folate levels change with response to androgen deprivation. Students' t test on continuous variables and Chi-squared test on dichotomous variables was performed along with Kaplan-Meier for time to event analysis.ResultsWe identified 56 men with prostate cancer undergoing androgen deprivation in which folate levels had been determined. 15 out of 16 (94%) men initiating ADT had increases in their folate, which is substantially more than 67% in maintenance group (P = 0.04). We identified more rapid time to death from prostate cancer if folate levels increased to levels >200 ng/ml above their baseline (P = 0.03). Mice models demonstrated a significant rise in serum red blood cell folate after mice were castrated (P = 0.03) by an average of 1.5x over pre-castrated baseline level. By contrast, sham-castrated mice showed no increase in serum folate levels over baseline.ConclusionOur study suggests that men with substantial rises in folate after initiating ADT may be associated with worse prostate cancer-specific and overall survival. Our translational experiments in mice confirmed correlation between rising in folate levels post-castration. Given this study, further investigation is warranted on the role of dietary folate consumption during initiation of ADT and progression to castrate-resistant prostate cancer.

Project description:ContextDespite a lack of data, increasing numbers of patients are receiving primary androgen deprivation therapy (PADT) as an alternative to surgery, radiation, or conservative management for the treatment of localized prostate cancer.ObjectiveTo evaluate the association between PADT and survival in elderly men with localized prostate cancer.Design, setting, and patientsA population-based cohort study of 19,271 men aged 66 years or older receiving Medicare who did not receive definitive local therapy for clinical stage T1-T2 prostate cancer. These patients were diagnosed in 1992-2002 within predefined US geographical areas, with follow-up through December 31, 2006, for all-cause mortality and through December 31, 2004, for prostate cancer-specific mortality. Instrumental variable analysis was used to address potential biases associated with unmeasured confounding variables.Main outcome measuresProstate cancer-specific survival and overall survival.ResultsAmong patients with localized prostate cancer (median age, 77 years), 7867 (41%) received PADT, and 11,404 were treated with conservative management, not including PADT. During the follow-up period, there were 1560 prostate cancer deaths and 11,045 deaths from all causes. Primary androgen deprivation therapy was associated with lower 10-year prostate cancer-specific survival (80.1% vs 82.6%; hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.03-1.33) and no increase in 10-year overall survival (30.2% vs 30.3%; HR, 1.00; 95% CI, 0.96-1.05) compared with conservative management. However, in a prespecified subset analysis, PADT use in men with poorly differentiated cancer was associated with improved prostate cancer-specific survival (59.8% vs 54.3%; HR, 0.84; 95% CI, 0.70-1.00; P = .049) but not overall survival (17.3% vs 15.3%; HR, 0.92; 95% CI, 0.84-1.01).ConclusionPrimary androgen deprivation therapy is not associated with improved survival among the majority of elderly men with localized prostate cancer when compared with conservative management.

Dataset Information

Undetectable prostate-specific antigen after short-course androgen deprivation therapy for biochemically recurrent patients correlates with metastasis-free survival and prostate cancer-specific survival.

Publications

Undetectable prostate-specific antigen after short-course androgen deprivation therapy for biochemically recurrent patients correlates with metastasis-free survival and prostate cancer-specific survival.

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