Timing Of Androgen Deprivation Therapy Research Articles

Replicating the timing of androgen deprivation therapy randomized trial (TROG 03.06 and VCOG PR 01-03 [TOAD]) for recurrent prostate cancer using real-world observational data.

e17090 Background: The landmark TOAD trial (Lancet Oncol 2016) demonstrated an overall survival benefit for immediate compared to delayed androgen deprivation therapy (ADT) for patients with recurrent prostate cancer or unsuitable for curative treatment. However, the extent to which TOAD trial results can be replicated in real-world population-based observational data is unknown. For these reasons, we used TOAD trial data and criteria to define a similar retrospective cohort of men with rising PSA after definitive treatment of localized prostate cancer to compare immediate versus delayed ADT for recurrent non-metastatic disease. Methods: We used two data sources to conduct this study: 1) TOAD trial data, and 2) national electronic health record, cancer registry, administrative, pharmacy, and laboratory data for men treated with radical prostatectomy or radiotherapy for localized prostate cancer and laboratory confirmed biochemical recurrence (BCR) between 2005- 2015 in the Veterans Health Administration. We defined BCR according to guidelines and used National Death Index data through 2019 for survival outcomes. We designated randomization to the ‘immediate’ and ‘delayed’ arms for men receiving ADT within (immediate) or after (delayed) 2 years of BCR in the observational data. We used Cox proportional hazards regression models adjusting for age, PSA at BCR, comorbidities, and Gleason score, stratified by prior ADT exposure, to compare survival outcomes for immediate versus delayed ADT. Results: We identified 9,866 men with BCR after radical prostatectomy, 3,431 after radiotherapy alone, and 2,703 after radiotherapy and adjuvant ADT. The mean age at randomization for the TOAD cohort was older (74.8 vs. 75.9 years, delayed vs. immediate) compared to our observational cohort (68.1 vs. 67.0 years, delayed vs. immediate). In unadjusted survival analyses, we found both overall and prostate cancer-specific survival were higher among patients with delayed ADT (log-rank p-value < 0.001 for both). Our multivariable survival models among men with and without prior ADT exposure also demonstrated survival benefit associated with delayed ADT (prior ADT exposure, adjusted hazard ratio (aHR) 2.3, 95% confidence interval (CI) 1.7, 3.0, no prior ADT exposure 2.6, 95% CI 2.4, 2.8). Conclusions: The benefit of immediate ADT administration compared to delayed as reported within the TOAD study was not found in a comparable observational cohort of men with non-metastatic recurrent prostate cancer. Even after multivariable adjustment, we found clear association of delayed ADT administration with improved survival outcomes suggesting selection bias and unobserved confounding, or that delayed ADT may be warranted for selected patient populations necessitating further investigation. Source of Funding: NCI R01 CA242559.

Assessing racial differences in time to treatment escalation following androgen-deprivation therapy among veterans with prostate cancer.

5078 Background: Androgen deprivation therapy (ADT) is standard care first-line (1L) systemic treatment for advanced and metastatic prostate cancer (PC). Currently, there are no population-level studies assessing the duration of 1L ADT and time to treatment escalation (chemotherapy [CT], novel hormonal therapy [NHT], or non-steroidal antiandrogen [NSAA]). Methods: We performed a retrospective population-level analysis to assess the association between race and time to treatment escalation after ADT in the Veterans Affairs Health Care System. From 2001-2021, 164,477 patients (pt) diagnosed with PC and treated with ADT alone were identified. Baseline demographic and clinical characteristics were sorted by race: Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Hispanic, Other and compared among groups using chi square tests for categorical variables and Kruskal-Wallis tests for continuous variables. The primary outcome was time from ADT to treatment escalation, defined as receipt of NHT, NSAA, or CT. Men with no evidence of treatment escalation were censored at time of death or most recent visit. We estimated 5-year event rates by race using Kaplan-Meier (KM) analyses. Univariable and multivariable Cox proportional hazards models were used to test the association between race and time to treatment escalation with time of ADT as time zero. Multivariable models were adjusted for age, year, time from PC diagnosis to ADT, Charlson Comorbidity Index and BMI at ADT start along with PSA, testosterone level, and receipt of radiation therapy (RT) prior to ADT. Results: NHB were youngest (p<0.001), started ADT in more recent years (p<0.001), had the highest pre-ADT PSA (p<0.001) and testosterone levels (p<0.001), the most comorbidities (p<0.001), and the highest rate of RT prior to ADT (p<0.001) relative to other groups. During a median (Q1, Q3) follow-up of 55.2 (25.0, 102.4) months, 31,288 pt (19%) had treatment escalation, of which 12,093 (39%) were NHTs, 14,842 (47%) were NSAAs, 3,895 (12%) were CT and 458 (2%) were other 2nd line therapies. Compared to NHW, NHB had significantly lower rate of treatment escalation in univariable (HR=0.89, 95% CI=0.87-0.92) and multivariable analysis (HR=0.82, 95% CI=0.80-0.84). KM estimates at 5-year for the percent free from escalation was 80.5 (80.2-80.8%) in NHW vs. 83.0 (82.6-83.4%) in NHB. Rate of treatment escalation was similar for Hispanics and other races compared to NHW, with 5-year KM estimates of 81.0 (80.3-81.7%) and 81.0 (80.0-82.0%) for Hispanics and other races, respectively. Conclusions: This study assessing racial differences in time to treatment escalation of men receiving 1L ADT found that NHB had a significantly lower rate of treatment escalation. Whether this decreased rate of treatment escalation among NHB men represents improved outcomes (i.e. lower risk of progression) or undertreatment requires further study.

Testosterone (T) recovery profiles after short-term androgen deprivation therapy (ADT)

ABSTRACT Introduction ADT plays a major role in several scenarios for men with prostate cancer. T recovery after ADT cessation may be incomplete with 10% of men estimated to suffer persistent castrate levels after long-term ADT. Objective The objective of this study was to evaluate T recovery after short courses of ADT. Methods Study population included men treated with ≤6 months of ADT in association with radiation therapy (RT). Early morning T levels were collected at baseline and periodically after ADT cessation. T recovery after ADT cessation was analyzed in 2 ways: improvement to non-castrate level (T ≥50 ng/dL), and recovery to normal (T ≥ 300 ng/dL). Recovery rates and median survival time were estimated using Kaplan-Meier statistics and predictors analyzed using Cox proportional hazard ratios. Results 88 men with a mean age of 68 ± 8 years at time of ADT were analyzed. Median duration of ADT was 3.1 months; 56% had an ADT duration between 1-3 months and 44% between 4-6 months. Mean pre-ADT T level was 390 ± 158 ng/dL. After cessation of ADT, median time to non- castrate levels was 9.3 (IQR = 6.3 – 18.5) months and 15.8 (IQR = 8.3 - 33.8) ‘months for recovery to T ≥300 ng/dL. Higher baseline T levels (T > 400 ng/dL) was associated with a faster recovery to normal T level (HR = 1.80, 95% CI = 1.09 – 2.95), but not to non-castrate level. Neither age > 65 years, prevalent diabetes, nor ADT duration of 4-6 months vs ≤ 3 months were significantly associated with a slower T recovery. Conclusions Most of our patients remained with low T levels one year after the cessation of ADT. Higher baseline T was associated with faster T recovery to normal (T ≥ 300 ng/dL). Disclosure Work supported by industry: no.

MP36-02 TESTOSTERONE (T) RECOVERY PROFILES AFTER SHORT-TERM ANDROGEN DEPRIVATION THERAPY (ADT)

You have accessJournal of UrologySexual Function/Dysfunction: Medical, Hormonal & Non-surgical Therapy II (MP36)1 Sep 2021MP36-02 TESTOSTERONE (T) RECOVERY PROFILES AFTER SHORT-TERM ANDROGEN DEPRIVATION THERAPY (ADT) Jose M Flores, Bruno Nascimento, Nicole Benfante, Elizabeth Schofield, and John P Mulhall Jose M FloresJose M Flores More articles by this author , Bruno NascimentoBruno Nascimento More articles by this author , Nicole BenfanteNicole Benfante More articles by this author , Elizabeth SchofieldElizabeth Schofield More articles by this author , and John P MulhallJohn P Mulhall More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002045.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: ADT plays a major role in several scenarios for men with prostate cancer. T recovery after ADT cessation may be incomplete with 10% of men estimated to suffer persistent castrate levels after long-term ADT. The objective of this study was to evaluate T recovery after short courses of ADT. METHODS: Study population included men treated with ≤6 months of ADT in association with radiation therapy (RT). Early morning T levels were collected at baseline and periodically after ADT cessation. T recovery after ADT cessation was analyzed in 2 ways: improvement to non-castrate level (T≥50 ng/dL), and recovery to normal (T≥300 ng/dL). Recovery rates and median survival time were estimated using Kaplan-Meier statistics and predictors analyzed using Cox proportional hazard ratios. RESULTS: 88 men with a mean age of 68±8 years at time of ADT were analyzed. Median duration of ADT was 3.1 months; 56% had an ADT duration between 1-3 months and 44% between 4-6 months. Mean pre-ADT T level was 390±158 ng/dL. After cessation of ADT, median time to non- castrate levels was 9.3 (IQR=6.3–18.5) months and 15.8 (IQR=8.3-33.8) `months for recovery to T≥300 ng/dL. Higher baseline T levels (T>400 ng/dL) was associated with a faster recovery to normal T level (HR=1.80, 95% CI=1.09–2.95), but not to non-castrate level. Neither age >65 years, prevalent diabetes, nor ADT duration of 4-6 months vs ≤3 months were significantly associated with a slower T recovery. CONCLUSIONS: Most of our patients remained with low T levels one year after the cessation of ADT. Higher baseline T was associated with faster T recovery to normal (T≥300 ng/dL). Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e636-e636 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jose M Flores More articles by this author Bruno Nascimento More articles by this author Nicole Benfante More articles by this author Elizabeth Schofield More articles by this author John P Mulhall More articles by this author Expand All Advertisement Loading ...

The Impact of Comorbidity and Age on Timing of Androgen Deprivation Therapy in Men with Biochemical Recurrence after Radical Prostatectomy.

Older men with major comorbidities have higher risks of morbidity and mortality from androgen deprivation therapy, and the benefits of immediate androgen deprivation therapy after biochemical recurrence in these men are unclear. We assessed variation in timing of androgen deprivation therapy by age and comorbidity in a cohort of men with biochemical recurrence after radical prostatectomy. We analyzed 2,097 men with biochemical recurrence after radical prostatectomy from 2000 to 2017 in the VA SEARCH database. We ascertained age and Deyo-Charlson comorbidity index scores at biochemical recurrence. Kaplan-Meier analysis and multivariable logistic regression were used to determine association of age and Deyo-Charlson comorbidity index with prostate specific antigen at the initiation of androgen deprivation therapy. In Kaplan-Meier analysis with prostate specific antigen at androgen deprivation therapy as the outcome, median prostate specific antigen at androgen deprivation therapy initiation was 6.2 ng/ml (95% CI 5.1-7.1) across all patients but differed among those who received adjuvant/salvage radiation (3.6 ng/ml, 95% CI 2.8-4.3) and those who did not (12.1 ng/ml, 95% CI 9.6-15.2, p <0.001). In multivariable Cox regression, advanced age (p=0.03) but not worse comorbidity (p=0.25) was associated higher prostate specific antigen at initiation of androgen deprivation therapy. Across all patients, prostate specific antigen at androgen deprivation therapy was lower among those <60 years old (3.7 ng/ml, 95% CI 2.6-5.8) compared to those 60-64 (5.0 ng/ml, 95% CI 3.9-6.6), 65-69 (6.6 ng/ml, 95% CI 4.9-8.8), 70-74 (8.8 ng/ml, 95% CI 6.1-12.3) and ≥75 years old (14.1 ng/ml, 95% CI 5.5-37.8). In contrast, prostate specific antigen at androgen deprivation therapy was similar among comorbidity subgroups (Deyo-Charlson comorbidity index 0: 6.3 ng/ml, 95% CI 5.0-7.9 vs Deyo-Charlson comorbidity index 3 or higher: 5.6 ng/ml, 95% CI 4.1-7.4). In general, these relationships were consistent among subgroups receiving adjuvant/salvage radiation. Men with comorbid disease at increased risk of morbidity and mortality with androgen deprivation therapy often receive androgen deprivation therapy at low prostate specific antigen values.

Timing of Androgen Deprivation Therapy for Prostate Cancer Patients after Radiation: Planned Combined Analysis of Two Randomized Phase 3 Trials

The TOAD (TROG 03.06; NCT00110162) phase 3 randomized trial showed that immediate androgen deprivation therapy (IADT) improved overall survival (OS) and time to clinical progression compared with delayed ADT (DADT) in progressive or relapsed prostate cancer patients after radical radiation therapy (RT) or prostatectomy + RT. ELAAT (NCT00439751) was a similarly designed trial but failed to reach its accrual goal. The two investigative teams planned a combined analysis before ELAAT was activated. This combined analysis seeks to determine if IADT improves a number of clinical outcomes including overall survival. The PSA failures from TOAD and 78/79 patients accrued to ELAAT were combined (1 patient was excluded due to castrate resistant prostate cancer (CRPC)). Participants for both trials were randomized 1:1 to IADT or DADT. The primary endpoint was all-cause mortality by intention-to-treat. Secondary endpoints were cancer-specific mortality (CSM), local progression, distant progression, CRPC, and prostate cancer complications (PCC). A total of 261 patients from TOAD and 78 patients from ELAAT were followed a median of 5.0y. TOAD patients were younger (mean age 70.5 vs 73.8y) and more had a relapse-free interval <2y from RT (30% vs 10%). In the DADT arms, 63% received ADT a median of 1.58y for TOAD; 38% received ADT a median 1.65y for ELAAT. For patients receiving ADT, the mean pre-ADT PSAs were 3.52 and 30.2 ng/ml in the IADT and DADT arms of TOAD and 3.98 and 18.1 ng/ml in ELAAT. There were 60 deaths, 40 and 20 respectively. Overall, for IADT and DADT arms the proportions of deaths in each trial were 15%, 11%, 19% and 26%, 27% and 24%. All-cause mortality (HR 0.75, 95% CI 0.40, 1.41; p = 0.37) and CSM (HR 0.57, 95% CI 0.22, 1.49) were not statistically different between IADT and DADT. Time to local progression (survival time ratio 1.97, 95% CI 1.28, 3.04; p=0.002) and distant progression (survival time ratio 1.28, 95% CI 1.04, 1.58; p=0.02) was higher while PCC (3.7 v 7.5%, p=0.06) was lower with IADT. CRPC outcomes will be presented at conference. No difference in OS was detected between IADT and DADT in the combined analysis. A possible explanation is that ELAAT accrued older patients with lower risk of CSM and had a smaller difference in PSA between the IADT and DADT arms. Not all relapsed men need IADT; many will die without ever needing ADT and never have a complication or develop CRPC. Further work is needed to identify patients who will benefit from IADT and those suitable for DADT.

Timing of androgen deprivation therapy for prostate cancer patients after radiation: Planned combined analysis of two randomized phase 3 trials.

5018Background: The TOAD (TROG 03.06; NCT00110162) phase 3 randomized trial showed that immediate androgen deprivation therapy (IADT) improved overall survival (OS) and time to clinical progression...

Prognostic factors in men receiving androgen deprivation therapy (ADT) for recurrent prostate cancer: Using absolute PSA and PSA doubling time (DT) to guide timing of ADT initiation.

129 Background: ADT is the first-line treatment for men experiencing recurrence after undergoing radical therapy for prostate cancer. However, timing of ADT initiation is controversial and there are limited data on prognostic factors in patients starting ADT. Methods: We identified consecutive men who underwent radical prostatectomy (RP) for localized prostate cancer at our institution between 1987 and 2007 and who subsequently received salvage ADT. Early progression on ADT was defined as development of metastatic disease within 2yrs of initiation. The primary outcomes of interest were cancer-specific (CSS) and overall survival (OS). Results: A total of 2418 men were included. Median age at RP was 64yrs and median follow-up was 13.9yrs. 48% and 20% of men had pathologic Gleason scores of 7 and 8-10 respectively. The median PSA was 2.6ng/ml, while 385 men (16%) had metastatic disease at receipt of ADT. Overall, 1060 men (44%) developed clinical metastases, with 625 (59%) of these doing so within 2yrs of starting ADT. On multivariable analysis, longer PSA DT before ADT was associated with lower odds of early progression on ADT (DT 3-9mths, OR = 0.19; DT ≥9mths, OR = 0.10, both p &lt; 0.001). 10- and 20-year CSS were 89% and 70%, and 10- and 20-year OS were 82% and 40% respectively. Independent predictors of lower CSS included metastatic disease at time of ADT (HR = 2.60), PSA at ADT of 5-50ng/ml (HR = 2.68) and &gt; 50ng/ml (HR = 4.33, all p &lt; 0.001), while longer PSA DT was associated with higher CSS (DT 3-9mths, HR = 0.54; DT ≥9mths, HR = 0.45, both p &lt; 0.001). PSA at ADT of 5-50ng/ml (HR = 3.10) and &gt; 50ng/ml (HR = 5.20, both p &lt; 0.001) were independent predictors of OS. Conclusions: PSA DT &lt; 3mths and absolute PSA at ADT initiation of ≥ 5ng/ml are adverse prognostic indicators in men receiving salvage ADT for relapse after RP. For patients with these features, their risk of early progression and death should be part of a discussion about the timing of ADT and consideration given to more aggressive treatment strategies. Conversely, men with biochemical relapse who have longer DT and PSA &lt; 5ng/ml are at lower risk and could make an informed decision to defer ADT initiation.

Outcomes in patients (Pts) with advanced prostate cancer and inactivating germline mutations in BRCA2 or ATM.

242 Background: Germline mutations in homologous recombination repair (HRR) genes, including BRCA2, are present in 6-12% of pts with metastatic castration-resistant prostate cancer (mCRPC). BRCA2 germline mutations are associated with high-grade and poor-prognosis localized disease, while outcomes in pts with advanced prostate cancer continue to be defined. Methods: Germline DNA from 536 consecutive mCRPC pts in our liquid biopsy program were screened for BRCA2 and ATM gene mutations using targeted sequencing. Kaplan-Meier curves were used to estimate the median time from androgen deprivation therapy (ADT) initiation to mCRPC, progression free survival (PFS) on first-line androgen receptor (AR) targeted therapy, and overall survival (OS). Outcomes in BRCA2 or ATM germline mutation carriers and a subset of the total sample of HRR wild-type (WT) pts, who had clinical data available (n = 113), were compared using the log-rank test. Results: 26/536 (4.9%) of pts had germline BRCA2 (n = 22) or ATM mutations (n = 4). After ADT initiation, HRR mutated pts progressed to mCRPC with a median time of 13.4 mo compared to 19.0 mo in WT pts (HR = 1.6, [95% CI 1.0-2.5], p = 0.03). HRR mutated pts had a median PFS on first-line AR-targeted therapy in the mCRPC setting of 3.3 mo versus 7.9 mo in WT pts (HR = 2.2, [95% CI 1.3-3.5], p = 0.002). OS for HRR mutated pts from the time of ADT was 57.7 mo in contrast to 104.9 mo in WT pts (HR = 1.8, [95% CI 1.0-3.4], p = 0.07). OS from time of CRPC was 29.7 mo in HRR mutated pts versus 50.3 mo in WT pts (1.6, [95% CI 0.8-2.9], p = 0.16). Conclusions: Germline HRR mutated pts perform poorly with shorter PFS on first-line AR-targeted therapy and time to mCRPC, in contrast to WT pts. These findings support the hypothesis that BRCA2 and ATM gene mutated pts have poor outcomes with current AR-targeted treatments and should be evaluated for alternate regimens.

The impact of timing of salvage hormonal therapy on survival after brachytherapy for prostate cancer

PurposeWe aimed to evaluate the impact of timing of androgen deprivation therapy (ADT) on survival in a cohort of patients with biochemical recurrence (BCR) after brachytherapy treatment for prostate cancer. Methods and MaterialsWe retrospectively identified 2366 men receiving permanent prostate brachytherapy with or without external beam radiation therapy. Patients experiencing BCR were stratified by receipt of immediate or delayed (≥3 months) ADT and prostate-specific antigen (PSA) failure threshold of 10 ng/mL. Prostate cancer–specific mortality (PCSM) and all-cause mortality (ACM) were evaluated using Fine–Gray's competing risks regression and Cox proportional hazard model, respectively. ResultsWe identified 109 patients in the study cohort treated with ADT for BCR, followed for a median of 11.4 years. Competing risk regression revealed that there was no difference in PCSM for patients receiving delayed vs. immediate ADT (hazard ratio [HR], 0.94; 95% confidence interval [CI]: 0.44–2.00: p = 0.871) or for those initiating hormonal therapy at PSA threshold of 10 vs. <10 ng/mL (HR, 0.85; 95% CI: 0.41–1.75; p = 0.649); similarly, there was no difference in ACM. PSA doubling time <6 months (HR, 2.52; 95% CI: 1.22–5.23; p = 0.013), time to BCR <3 years (HR, 3.27; 95% CI: 1.67–6.42; p = 0.003), and permanent prostate brachytherapy with external beam radiation therapy (HR, 5.21; 95% CI: 2.05–13.26; p = 0.001) were significantly associated with PCSM, as well as ACM. ConclusionsAmong a cohort of brachytherapy patients, we identified no significant difference in survival for delayed salvage hormonal therapy. Shorter PSA doubling time and time to BCR are significantly associated with adverse outcomes, and these patients should be considered for immediate salvage therapy.

Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial

Androgen-deprivation therapy is offered to men with prostate cancer who have a rising prostate-specific antigen after curative therapy (PSA relapse) or who are considered not suitable for curative treatment; however, the optimal timing for its introduction is uncertain. We aimed to assess whether immediate androgen-deprivation therapy improves overall survival compared with delayed therapy. In this randomised, multicentre, phase 3, non-blinded trial, we recruited men through 29 oncology centres in Australia, New Zealand, and Canada. Men with prostate cancer were eligible if they had a PSA relapse after previous attempted curative therapy (radiotherapy or surgery, with or without postoperative radiotherapy) or if they were not considered suitable for curative treatment (because of age, comorbidity, or locally advanced disease). We used a database-embedded, dynamically balanced, randomisation algorithm, coordinated by the Cancer Council Victoria, to randomly assign participants (1:1) to immediate androgen-deprivation therapy (immediate therapy arm) or to delayed androgen-deprivation therapy (delayed therapy arm) with a recommended interval of at least 2 years unless clinically contraindicated. Randomisation for participants with PSA relapse was stratified by type of previous therapy, relapse-free interval, and PSA doubling time; randomisation for those with non-curative disease was stratified by metastatic status; and randomisation in both groups was stratified by planned treatment schedule (continuous or intermittent) and treatment centre. Clinicians could prescribe any form and schedule of androgen-deprivation therapy and group assignment was not masked. The primary outcome was overall survival in the intention-to-treat population. The trial closed to accrual in 2012 after review by the independent data monitoring committee, but data collection continued for 18 months until Feb 26, 2014. It is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12606000301561) and ClinicalTrials.gov (NCT00110162). Between Sept 3, 2004, and July 13, 2012, we recruited 293 men (261 with PSA relapse and 32 with non-curable disease). We randomly assigned 142 men to the immediate therapy arm and 151 to the delayed therapy arm. Median follow-up was 5 years (IQR 3·3-6·2) from the date of randomisation. 16 (11%) men died in the immediate therapy arm and 30 (20%) died in the delayed therapy arm. 5-year overall survival was 86·4% (95% CI 78·5-91·5) in the delayed therapy arm versus 91·2% (84·2-95·2) in the immediate therapy arm (log-rank p=0·047). After Cox regression, the unadjusted HR for overall survival for immediate versus delayed arm assignment was 0·55 (95% CI 0·30-1·00; p=0·050). 23 patients had grade 3 treatment-related adverse events. 105 (36%) men had adverse events requiring hospital admission; none of these events were attributable to treatment or differed between treatment-timing groups. The most common serious adverse events were cardiovascular, which occurred in nine (6%) patients in the delayed therapy arm and 13 (9%) in the immediate therapy arm. Immediate receipt of androgen-deprivation therapy significantly improved overall survival compared with delayed intervention in men with PSA-relapsed or non-curable prostate cancer. The results provide benchmark evidence of survival rates and morbidity to discuss with men when considering their treatment options. Australian National Health and Medical Research Council and Cancer Councils, The Royal Australian and New Zealand College of Radiologists, Mayne Pharma Australia.

Serum testosterone level predicts the effective time of androgen deprivation therapy in metastatic prostate cancer patients.

Androgen deprivation therapy (ADT) is the standard of care for patients with metastatic prostate cancer. However, whether serum testosterone levels, using a cut-off point of 50 ng dl−1, are related to the effective time of ADT in newly diagnosed prostate cancer patients remains controversial. Moreover, recent studies have shown that some patients may benefit from the addition of upfront docetaxel chemotherapy. To date, no studies have been able to distinguish patients who will benefit from the combination of ADT and docetaxel chemotherapy. This study included 206 patients who were diagnosed with metastatic prostate cancer and showed progression to castrate-resistance prostate cancer (CRPC). Serum testosterone levels were measured prospectively after ADT for 1, 3, and 6 months. The endpoint was the time to CRPC. In univariate and multivariate analyses, testosterone levels <50 ng dl−1 were not associated with the effective time of ADT. Receiver operating characteristic and univariate analysis showed that testosterone levels of ≤25 ng dl−1 after the first month of ADT offered the best overall sensitivity and specificity for prediction of a longer time to CRPC (adjusted hazard ratio [HR], 1.46; 95% confidence interval [95% CI], 1.08–1.96; P = 0.013). Our results show that serum testosterone level of 25 ng dl−1 plays a prognostic role in prostate cancer patients receiving ADT. A testosterone value of 25 ng dl−1 after the first month of ADT can distinguish patients who benefit from ADT effectiveness for only a short time. These patients may need to receive ADT and concurrent docetaxel chemotherapy.

Alpha/beta (α/β) ratio for prostate cancer derived from external beam radiotherapy and brachytherapy boost.

There is disagreement regarding the value of the α/β ratio for prostate cancer. Androgen deprivation therapy (ADT) may dominate the effects of dose fractionation on prostate-specific antigen (PSA) response and confound estimates of the α/β ratio. We estimate this ratio from combined data on external beam radiation therapy (EBRT) and brachytherapy (BT)-treated patients, providing a range of doses per fraction, while accounting for the effects of ADT. We analyse data on 289 patients with local prostate cancer treated with EBRT (2 Gy per fraction) or EBRT plus one or two BT boosts of 10 Gy each. The timing of ADT was heterogeneous. We develop statistical models to estimate the α/β ratio based upon PSA measurements at 1 year as a surrogate for the surviving fraction of cancer cells as well as combined biochemical + clinical recurrence-free survival (bcRFS), controlling for ADT. For the PSA-based end point, the α/β ratio estimate is 7.7 Gy [95% confidence interval (CI): 4.1 to 12.5]. Based on the bcRFS end point, the estimate is 18.0 Gy (95% CI: 8.2 to ∞). Our model-based estimates of the α/β ratio, which account for the effects of ADT and other important confounders, are higher than some previous estimates. Although dose inhomogeneities and other limitations may limit the scope of our findings, the data suggest caution regarding the assumptions of the α/β ratio for prostate cancer in some clinical environments.

Falls and frailty in prostate cancer survivors on androgen deprivation therapy.

134 Background: Androgen deprivation therapy (ADT) treatment for prostate cancer is associated with muscle loss, weakness and weight gain that could lead to falls and frailty, but the prevalence of these conditions in prostate cancer survivors (PCS) is poorly understood. The aim of this study is to describe the prevalence of falls and frailty in PCS on ADT and their associations with modifying factors, such as age and timing of ADT. Methods: Health history, cancer treatment and falls were self-reported by 146 PCS on ADT (mean age: 74+8 years). ADT usage and current versus past usage was confirmed against electronic medical records. Frailty was determined by self-report to 5 questions asking about presence or absence of fatigue, weakness, mobility difficulty, comorbidities, and weight loss, which could represent sarcopenia. Presence of each condition was summed to categorize men into one of three frailty phenotypes: frail (3-5), pre-frail (1-2) or not frail (0) groups. Since fat gain, rather than weight loss, is common with ADT and can impact function we also recalculated frailty as an “obese frailty” phenotype substituting obesity (BMI &gt; 30 kg/m2) for weight loss. Comparisons were performed using chi-square. Results: 38% of PCS on ADT experienced a fall in the past year and among fallers, 61% experienced a fall that resulted in an injury. Using the frailty phenotype, 29% of PCS were pre-frail and 10% were frail; however, using the obese frailty phenotype, 47% of PCS were pre-frail and 15% were frail. The absence of frailty was significantly less in older men than younger men using the frail (p = 0.013), but not obese frail phenotype (p = 0.54). Fall and frailty rates did not significantly differ between PCS who were current versus past users of ADT (p = 0.65 and 0.26 for falls and frailty, respectively). Conclusions: Regardless of the frailty phenotype used, the rate of falls and prevalence of frailty among PCS on ADT was greater than fall rate (25%) and the frailty prevalence (4%) reported in large community-based samples of similarly aged men. These data also suggest that falls and frailty may continue after men stop ADT use. Research to identify risk factors for falls and frailty in PCS on ADT is warranted so that effective interventions can be developed and tested.

The impact of increasing dose on overall survival in prostate cancer.

PurposeTo assess the impact of increasing dose on overall survival (OS) for prostate cancer patients.MethodsTreatment data were obtained on more than 20,000 patients in the National Oncology Data Alliance®, a proprietary database of merged tumor registries, who were treated for prostate cancer with definitive radiotherapy between 1995 and 2006. Eligible patients had complete data on total dose, T stage, use and timing of androgen deprivation therapy (ADT), and treatment start date (n = 20,028). Patients with prior malignancies were excluded.ResultsOn multivariate analysis, dose, T stage, grade, marital status, age, and neoadjuvant ADT were significant predictors of OS. Hazard ratios for OS declined monotonically with increasing dose, reaching 0.63 (95 % Confidence Interval 0.53–0.76) at ≥80 Gy. On subset analysis, neoadjuvant ADT significantly improved OS in high risk patients but was not significant in lower risk patients. The dose response was maintained across all risk groups. Medical comorbidities were balanced across all dose strata and sensitivity analysis demonstrated that other prognostic factors were unlikely to explain the observed dose response.ConclusionsThis study suggests that increasing dose significantly improves OS in prostate cancer patients treated with radiotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-015-0419-3) contains supplementary material, which is available to authorized users.

TROG 03.06 and VCOG PR 01-03: The "timing of androgen deprivation therapy in prostate cancer patients with a rising PSA (TOAD)" collaborative randomised phase III trial.

5007 Background: This randomized, prospective phase III trial investigated if immediate intervention with androgen deprivation therapy (ADT) (Arm B) improved overall survival compared to delayed AD...

Management of Node Only Recurrence after Primary Local Treatment for Prostate Cancer: A Systematic Review of the Literature

We analyzed all available studies assessing the management of node only recurrence after primary local treatment of prostate cancer. We systematically reviewed the literature in January 2015 using the PubMed, Web of Sciences and Embase databases according to PRISMA guidelines. Studies exclusively reporting visceral or bone metastatic disease were excluded from analysis. Eight radiotherapy and 12 salvage lymph node dissection series were included in our qualitative study. All 248 radiotherapy and 480 salvage lymph node dissection studies were single arm case series including a total of 728 patients. Choline positron emission tomography/computerized tomography was the reference imaging technique for nodal recurrence detection. Globally 50% of patients remained disease-free after short-term followup. Nevertheless, approximately two-thirds of patients received adjuvant hormone therapy, leading an overestimation of prostate specific antigen-free survival rates obtained after salvage treatment. Combining radiotherapy with salvage lymph node dissection may improve oncologic control in the treated region without improving the outfield relapse risk or the prostate specific antigen response. Great heterogeneity among series in adjuvant treatments, endpoints, progression definitions and study populations made it difficult to assess the precise impact of salvage treatment on the prostate specific antigen response and compare outcomes between radiotherapy and salvage lymph node dissection series. Toxicity after radiotherapy or salvage lymph node dissection was acceptable without frequent high grade complications. The benefit of early hormone therapy as the only salvage treatment remains unknown. Although a high level of evidence is currently missing to draw any strong conclusion, published clinical series show that in select patients salvage treatment directed to nodal recurrence could lead to good oncologic outcomes. Although the optimal timing of androgen deprivation therapy in this setting is still unknown, such an approach could delay time to systemic treatment with an acceptable safety profile. Future prospective trials are awaited to better clarify this potential impact on well-defined endpoints.

Apoptotic activity in patient serum while on an acai juice product in the setting of a slowly rising PSA.

e16055 Background: For patients with a slowly rising PSA, the timing of androgen deprivation therapy (ADT) initiation is highly debated given the long term side effects. In this setting, numerous nutraceuticals, or plant derivatives, such as grape seed, milk thistle, or pomegranate have been shown to slow the growth of prostate cancer (PCa). The acai berry has been shown to be rich in flavinoids with high antioxidant properties and was evaluated in this phase II single-institution study in asymptomatic PCa patients with a rising PSA. The primary endpoint was decline in PSA of 50% from baseline. While flavinoids have been shown to induce cell cycle arrest, understanding the actions of the mix of phytochemicals has not been rigorously undertaken for the acai berry. It has shown proapoptotic effects in vitro on leukemic cell lines, and decreased cytokine production correlated with subsequent anti-esophageal tumorogenesis effects in vivo. In order to better understand the mechanism of action of acai, patient serum samples were analyzed in vitro. Methods: While on trial, patients consumed 2oz of acai juice product daily for 30 weeks. Two serum samples were drawn at weeks 0, 2, 6, and 18 for correlative analysis with the M30 Apoptosense ELISA. This measures caspase cleaved Keratin18 (ccK18) as a marker of early apoptotic activity. Results: An increase from baseline in ccK18 was seen at 2 weeks in a majority of patients (13/19; p= 0.12). Additionally, the one clinical responder on trial had a significantly higher level of ccK18 throughout the trial with a peak at week 6. Baseline ccK18 values did not correlate with clinical outcome (Spearman coefficient r=-0.13, p=0.6). Conclusions: Nutraceuticals may offer a well-tolerated treatment option for slowing the growth of prostate cancer as evidenced by the prolongation in doubling time in 86% of patients in this trial. The rise of ccK18 at week 2 and elevated levels in the responder’s serum suggest there is a pro-apoptotic treatment effect with acai. Additional cytokine analysis, and ratio of necrotic death to apoptotic death is underway in order to compare additional mechanisms. This initial evaluation offers early insight of the mechanism of action of acai in PCa.

Use of elevated baseline IL-8, CCL-2, and TNFα to predict for shorter overall survival (OS) in men with metastatic prostate cancer initiating androgen-deprivation therapy (ADT).

13 Background: Inflammation associated chemokines and cytokines have been shown in preclinical models to lead to the induction of castration resistance. We assessed whether higher blood cytokines and chemokines were associated with shorter time to CRPC and OS in patients initiating ADT for metastatic prostate cancer. Methods: A retrospective analysis of inflammatory markers including IL1β, IL-6, IL-8, TNFα and CCL-2 was undertaken in men initiating ADT for metastatic prostate cancer. Proteins were measured using multiplex electrochemiluminescence assays. The analytical cohort of 122 patients included a prospective trial (50 patients) and chart review (72 patients). A multivariate COX model was used to investigate the relationship between serum markers of inflammation and time to CRPC and OS. The covariates were age at time of ADT, ECOG score, race, baseline PSA, and extent of disease. Results: At time of initiating ADT, the median age of the cohort was 67 years, median PSA was 27.4, 82% had an ECOG PS of 0, 62% had extensive metastatic disease and 91% were Caucasian. Median OS was 42.2 months. The median (med) baseline levels for IL8 was 9.3pg/ml, TNFα was 2.4 pg/ml and CCL-2 was 507.5 pg/ml. As detailed below, patients with elevated IL-8, TNFα and CCL-2 had a significantly shorter OS and showed a non-significant shorter time to CRPC. Conclusions: In men with metastatic prostate cancer starting ADT, higher serum inflammatory markers are associated with poorer OS. This correlative data suggests that anti-inflammatory strategies which improved ADT efficacy in preclinical models may be relevant to the clinical setting. [Table: see text]

Use of elevated insulin-like growth factor binding protein-1 (IGFBP-1) to predict outcomes in men with metastatic prostate cancer treated with androgen-deprivation therapy (ADT).

191 Background: IGF-1 has been shown to promote cancer growth by activation of PI3 kinase and downregulation of AMPK. IGFBP-1 shuttles IGF-1 across blood vessel membranes. Elevated IGFBP-1 blood levels may be indicative of tissue IGF-1 levels and has been associated with prostate cancer risk. We hypothesized that IGF-1 and IGFBP-1 blood levels might effect ADT efficacy. Methods: A retrospective analysis of IGF-1 and IGFBP-1 was undertaken in men commencing ADT for metastatic prostate cancer. Blood was drawn within one month of initiating ADT and stored. Proteins were measured using multiplex electrochemiluminescence assays. A cohort of 122 patients was compiled from a prospective trial (50 patients) and chart review (72 patients). A multivariate analysis (MVA) using a COX model was performed to identify associations between blood levels of the markers and time to the development of castration resistant prostate cancer (CRPC) and overall survival (OS). The covariates analyzed were age at time of ADT, ECOG score, race, baseline PSA, and extent of disease. Results: At time of initiating ADT the cohort had a median age of 67 years, PSA of 27.4 and 82% had ECOG 0. 91% were Caucasian. 62% had extensive metastatic disease. Median OS was 42.2 months. The median (med) baseline levels for IGF-1 was 75.6 ng/ml and for IGFBP-1 was 1844 pg/ml. As detailed in the table, patients with IGFBP-1 levels above the median had significantly shorter time to development of CRPC and OS on MVA. There was no association between IGF-1 levels and time to CRPC development or OS. Conclusions: Elevated levels of IGFBP-1 are associated with shorter duration of ADT efficacy in men with metastatic prostate cancer. This correlative data supports the ongoing SWOG trial assessing whether IGF signaling blockade improves ADT efficacy, as has been seen in preclinical models. [Table: see text]