Rapid Prostate-specific Antigen Doubling Time Research Articles

Survival and Economic Impact of Rapid Prostate-Specific Antigen Doubling Time in Patients With Nonmetastatic Castration-Resistant Prostate Cancer.

In patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), prostate-specific antigen doubling time (PSADT) is associated with risk of metastasis and survival. This study evaluated the association of PSADT with clinical and economic outcomes in a real-world setting among patients with nmCRPC not receiving novel hormonal therapy (NHT), using 2-month PSADT thresholds. We retrospectively identified Veterans Health Administration patients with nonmetastatic prostate cancer and ≥2 PSA increases after medical/surgical castration (2012-2016). The third measurement was the index (CRPC) date. Patients with ≥3 postindex PSA measurements, including index, were followed until death or ≥12 months until disenrollment, study end, or death, and grouped into 2-month cohorts based on postindex PSADT. Cox regression models assessed association between PSADT, time to metastasis, and death. Healthcare resource utilization and costs were evaluated. Among 2800 evaluable patients, median follow-up was 30 months and median PSADT was 17 months. Relative to the reference cohort (PSADT >12 months), all cohorts had significantly higher metastasis risk. PSADT ≤10-month cohorts had significantly greater mortality risk than the reference; hazard ratios (95% confidence intervals) ranged from 12.3 (9.2, 16.4) in the PSADT ≤2-month cohort to 1.3 (0.9, 2.0) in the >10 to ≤12-month cohort. Total costs were significantly higher for cohorts up to and including the PSADT >8 to ≤10-month cohort, than for the reference cohort. Mean per patient per month all-cause medical plus pharmacy costs were $6623, $4768, and $4049 in the PSADT ≤2-month, >2 to ≤4-month cohort, and >4 to ≤6-month cohorts, respectively, versus $1911 in the PSADT >12-month cohort (P <0.05). Most patients with nmCRPC have PSADT >12 months and a long natural history. For those with shorter PSADT, the risk of metastasis, death, and costs increased. These data can help select patients for NHT and conversely those who can safely delay NHT for nmCRPC.

PD16-12 REAL-WORLD OUTCOMES AMONG MEN WITH NONMETASTATIC CASTRATION-SENSITIVE BIOCHEMICAL RECURRENCE AFTER DEFINITIVE THERAPY WITH SHORT PSA DOUBLING TIME RECEIVING EARLY SECONDARY TREATMENT

You have accessJournal of UrologyCME1 Apr 2023PD16-12 REAL-WORLD OUTCOMES AMONG MEN WITH NONMETASTATIC CASTRATION-SENSITIVE BIOCHEMICAL RECURRENCE AFTER DEFINITIVE THERAPY WITH SHORT PSA DOUBLING TIME RECEIVING EARLY SECONDARY TREATMENT Stephen J Freedland, Wei Gao, Angela Lax, Hongbo Yang, Krishnan Ramaswamy, David Russell, Agnes Hong, and Jasmine Ivanova Stephen J FreedlandStephen J Freedland More articles by this author , Wei GaoWei Gao More articles by this author , Angela LaxAngela Lax More articles by this author , Hongbo YangHongbo Yang More articles by this author , Krishnan RamaswamyKrishnan Ramaswamy More articles by this author , David RussellDavid Russell More articles by this author , Agnes HongAgnes Hong More articles by this author , and Jasmine IvanovaJasmine Ivanova More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003271.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: There is no consensus on treatment (tx) for men with nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence (BCR) after definitive tx (radical prostatectomy or radiotherapy). We assessed outcomes in men with nmCSPC and short prostate-specific antigen doubling time (PSADT) following BCR after definitive tx. METHODS: We reviewed the Veterans Health Administration (VHA) database between January 1, 2006 and June 22, 2020 for men with nmCSPC and BCR (index date) after definitive tx. Men were required to have PSADT ≤15 months after index date and were categorized into rapid (≤9 months) and less rapid (>9 but ≤15 months) PSADT. Outcomes included time to first antineoplastic tx after BCR and metastasis-free survival (MFS; time to metastasis or death). Cox proportional models compared the rapid and less rapid PSADT cohorts. Adjusted models controlled for baseline demographic and clinical characteristics. RESULTS: 753 men with nmCSPC were included in the analysis (rapid, n=485; less rapid, n=268). The rapid PSADT men were younger, more likely to be White, and had shorter median time from definitive tx to index (Table 1). Versus less rapid PSADT, rapid PSADT men had shorter median time to first antineoplastic tx (11.3 vs. 29.3 months), and MFS (94.1 vs. not reached) after BCR. CONCLUSIONS: Most rapid PSADT men underwent secondary tx within 1 year of BCR compared with less rapid PSADT men (53.2% vs 16.2%), whereas most less rapid PSADT men remained tx free for >2 years. Importantly, median MFS in men with rapid PSADT was 94.1 months, closely approximating the Pound data from Hopkins, wherein median time to metastases after BCR was 96 months (8 years). However, the Pound data included all BCR patients, not just those with rapid PSADT. Also, in the Pound data, no patients received early hormonal tx, whereas most VHA patients received secondary tx within 1 year of BCR. While circumstantial, the fact that rapid PSADT VHA patients heavily treated with secondary tx had similar outcomes to all BCR patients in the Pound series where none received aggressive secondary tx suggests the potential benefit of aggressive early tx of men with rapid PSADT after BCR. Source of Funding: Pfizer © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e493 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Stephen J Freedland More articles by this author Wei Gao More articles by this author Angela Lax More articles by this author Hongbo Yang More articles by this author Krishnan Ramaswamy More articles by this author David Russell More articles by this author Agnes Hong More articles by this author Jasmine Ivanova More articles by this author Expand All Advertisement PDF downloadLoading ...

Detection Efficacy of 68Ga-PSMA-11 PET/CT in Biochemical Recurrence of Prostate Cancer with Very Low PSA Levels: A 7-Year, Two-Center "Real-World" Experience.

In biochemical recurrence of prostate cancer (BCR), prompt tumor localization guides early treatment, potentially improving patient outcomes. Gallium-68 prostate-specific membrane antigen-11 positron emission tomography/computed tomography (68Ga-PSMA-11 PET/CT) detection rates of lesions suspicious for prostate cancer are well known to rise along with prostate-specific antigen (PSA) concentration. However, published data are limited regarding very low values (≤0.2 ng/mL). We retrospectively analyzed ~7-year "real-world" experience in this setting in a large post-prostatectomy cohort (N = 115) from two academic clinics. Altogether 44 lesions were detected in 29/115 men (25.2%) (median [minimum-maximum] 1 [1-4]/positive scan). The apparent oligometastatic disease was found in nine patients (7.8%) at PSA as low as 0.03 ng/mL. Scan positivity rates were highest when PSA was >0.15 ng/mL, PSA doubling time was ≤12 months, or the Gleason score was ≥7b (in 83 and 107 patients, respectively, with available data); these findings were statistically significant (p ≤ 0.04), except regarding PSA level (p = 0.07). Given the benefits of promptly localizing recurrence, our observations suggest the potential value of 68Ga-PSMA-11 PET/CT in the very low PSA BCR setting, especially in cases with more rapid PSA doubling time or with high-risk histology.

Is time to castration resistant prostate cancer a potential intermediate end-point for time to metastasis among men initiating androgen deprivation therapy for non-metastatic prostate cancer with rapid PSA doubling time (

Metastasis-free survival (MFS) is a surrogate for overall survival (OS) in men with non-metastatic castration-resistant prostate cancer (CRPC), but this endpoint may take years to develop in men with non-metastatic castrate-sensitive disease. The study objective was to examine whether progression to CRPC is a potential intermediate endpoint for developing metastatic disease in patients with biochemical recurrence (BCR) after radical prostatectomy (RP). Men with BCR following RP who had PSA doubling times (PSADT) < 9 months and no metastasis at the time of initiating androgen deprivation therapy (ADT) (n = 210) were included. The primary objective was to assess the correlation between CRPC-free survival (CRPC-FS) and MFS, and the secondary objective was to assess the correlation between time to metastasis and time to CRPC. Kendall's Tau was used to test the correlation for the primary and secondary outcomes. The median MFS was 104 months (95% CI: 83-114) and median CRPC-FS was 100 months (95% CI: 80-114). Based on the Kaplan-Meier curve, the greatest difference in time to MFS and CRPC-FS was around 70% free survival, which was reached at 61.2 months for MFS and 49.6 months for CRPC-FS. Kendall's Tau for the correlation between CRPC-FS and MFS and between time to CRPC and time to metastasis was 0.867 (95% CI: 0.765-0.968) and 0.764 (95% CI: 0.644-0.884), respectively. Given the high correlation between CRPC-FS and MFS, after validation, CRPC-FS may serve as a potential intermediate endpoint in trials for men with BCR initiating ADT following local therapy.

A randomized phase Ib/II study of intermittent androgen deprivation therapy plus nivolumab with or without interleukin-8 blockade in men with hormone-sensitive prostate cancer (MAGIC-8).

5082 Background: Immunotherapy has limited efficacy in castration-resistant prostate cancer. Androgen deprivation therapy (ADT) has significant immunomodulatory effects and initially induces a complex immune infiltrate before castration-resistance develops. However, ADT also recruits immunosuppressive myeloid cells to the tumor microenvironment by increasing interleukin-8 (IL-8). We conducted a phase Ib/II clinical trial of immunotherapy plus ADT in men with recurrent castration-sensitive prostate cancer (CSPC). We hypothesized that anti-PD-1 (nivolumab) +/- anti-IL-8 (BMS-986253) given at the time of castration could induce anti-tumor immune responses and decrease disease progression. Methods: MAGIC-8 was a multicenter, phase Ib/II study evaluating nivolumab +/- BMS-986253 combined with a short course of degarelix acetate in patients with recurrent CSPC and rapid PSA doubling time (≤ 12 mos). In the Phase Ib portion, patients were treated with nivolumab (480mg Q4W) for 8 wks followed by nivolumab plus degarelix for an additional 16 wks. In the phase II portion, patients were randomized 1:2 to nivolumab + degarelix (Arm A) versus nivolumab + BMS-986253 (2400mg Q2W) + degarelix (Arm B). The primary endpoints were PSA recurrence at 10 mos following randomization and safety. Key secondary endpoints included biochemical recurrence-free survival (bPFS), time to recovery of testosterone (&gt; 150ng/dl), and bPFS after recovery of testosterone. Results: Between October 16, 2019 and March 9, 2021, 59 patients were enrolled. The first 15 patients were treated on Arm A followed by 1:2 randomization to Arm A (N = 15) versus Arm B (N = 29). Median follow up was 11.6 mos at the data cutoff (1/24/22). Patients treated on Arm A had a significantly lower rate of PSA relapse (17.39%) at 10 mos compared to historical controls (p = &lt; 0.001), including a subgroup of patients (6.67%) with recovery of testosterone and no PSA relapse at &gt; 2 years of follow up. Median time-to-recovery of testosterone was 12.7 mos, median bPFS was 14.0 mos and median bPFS after recovery of testosterone was 5.5 mos. In Arm B, there was no difference in PSA relapse at 10 mos (35%, p = 0.09), median time-to-recovery of testosterone, median bPFS and median bPFS after recovery of testosterone compared to historical controls. Treatment in both arms was well tolerated with a lower rate of grade 3-4 treatment-related adverse events in Arm B compared to Arm A (3.5% vs 12.9%). Conclusions: A short course of ADT plus nivolumab may decrease the rate of PSA relapse and lead to durable long-term responses after recovery of testosterone in a subset of patients. These data support further evaluation of combining nivolumab with ADT in CSPC. Although the addition of BMS-986253 did not improve rate of PSA relapse, we observed significantly less toxicity with the addition of IL-8 inhibition. Clinical trial information: NCT03689699.

A systematic review and network meta-analysis of FDA approved treatment options in men with nonmetastatic, castration-resistant prostate cancer (M0CRPC).

335 Background: Network meta-analysis can provide useful evidence for relative efficacy and toxicity of different treatment options in absence of head-to-head trials. Previously, we reported no difference in efficacy between Apalutamide (APA) and Enzalutamide (ENZA). In this analysis, we provide updated indirect comparisons of all FDA approved agents (APA,ENZA, Darolutamide(DARO) for the treatment of M0CRPC with rapid PSA doubling time. Methods: MEDLINE, EMBASE and Cochrane Library were searched to identify relevant clinical trials. Hazard ratios (HR) and 95% confidence interval (CI) for Metastasis Free Survival (MFS), Overall Survival (OS) and data on grade 3 or higher AEs were abstracted. Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 software (MRC Biostatistics Unit, Cambridge, UK) to perform an indirect comparisons. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: Three RCTs (SPARTAN, PROSPER and ARAMIS) compared APA, ENZA and DARO respectively in combination with ADT to ADT alone. A total of 4117 patients were included in efficacy analysis (2694 received novel hormonal agents and 1423 received ADT and placebo). There were no statistically significant differences in MFS (HR 0.97, 95% CrI 0.74 - 1.30) between APA and ENZA; however, both APA 0.69 (95% CI 0.52 -0.92) and ENZA 0.71 (95% CrI 0.53, 0.92) significantly improved MFS as compared to DARO. There were no statistically significant differences in OS between these drugs. DARO had fewer grade 3 or higher adverse events of fatigue (HR 0.09, 95% CrI 0.01 – 0.51) compared to ENZA. However other common adverse events such as hypertension, falls, coronary artery disease/myocardial infarction and diarrhea were not significantly different between treatment groups. There was low risk of bias amongst included studies. Conclusions: APNA and ENZA provide significant improved in MFS as compared to DARO in patients with M0CRPC. The drugs have similar toxicity profile except that DARO was associated with lower incidence of fatigue compared to ENZA. Cost effective analysis of these drugs will be reported separately.

Phase II trial of a DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) and nivolumab (Nivo) in patients (pts) with nonmetastatic, PSA-recurrent prostate cancer (PCa).

TPS273 Background: Radical prostatectomy (RP) and radiation therapy (RT) are the gold standard, curative intent treatment for pts with presumed organ-confined PCa. However, about one third of these pts will have progressive or metastatic disease at 10 years (yr). Pts with PSA recurrence without radiographic evidence of metastatic (m) PCa (stage M0) will ultimately develop radiographically apparent mPCa within a median of 8 yr. Pts with rapid PSA doubling time (DT) have a markedly shorter time to mPCa and death. Utilizing an immunotherapeutic approach could utilize the sensitivity and specificity of the immune system to treat microscopic disease and potentially avoid or postpone androgen deprivation therapy (ADT) and its unwanted side effects. Methods: In this single arm, two-stage phase II trial, a total of 21-41 PCa pts with PSA only progression (4 rising PSA with final PSA ≥ 2 ng/mL) after initial RP for presumed organ-confined disease who have no radiographic evidence of mPCa in conventional imaging (CT and bone scan) will be enrolled. Pts with small cell or other variant PCa, or history of ADT other than concurrent with RT are excluded. All pts will be treated with pTVG-HP 100 μg intradermally (id) and Nivo 240 mg IV every (Q) 2 weeks (w) x6, and then pTVG-HP 100 μg id and Nivo 480 mg IV Q4w x9 beginning w12 on study. Pts with PSA on w4 &gt; PSA on day 1 will additionally receive rhGM-CSF 208 μg id, as a vaccine adjuvant, Q2w x4 beginning w4 on study. Pts will be treated until progression or up to a total of 1 yr. Response will be monitored by CT and bone scan Q6 months or as clinically indicated. Primary endpoints are safety and tolerability of this combination and PSA complete response rate (PSA &lt; 0.2 ng/mL). Key secondary endpoints are 2-yr metastasis-free survival, median radiographic progression-free survival, PSA response rate (≤50% of baseline), and changes in PSA DT. Elicited antigen-specific T-cell and/or IgG response and its correlation with PSA response will be explored. Bone mets not detected by conventional imaging and their association with response will be evaluated by Quantitative Total Bone Imaging (QTBI) by NaF PET/CT. Updated enrollment will be presented. Clinical trial information: NCT03600350.

Darolutamide For Castration-Resistant Prostate Cancer.

The treatment landscape of advanced prostate cancer continues to evolve rapidly, with newer and more active drugs being used in earlier phases of the disease based on improved overall survival. After adoption of docetaxel for metastatic castration-sensitive disease, large trials with next-generation androgen receptor-signaling inhibitors (abiraterone, enzalutamide and apalutamide) have demonstrate significant improvements in survival and important secondary endpoints. For non-metastatic castration-resistant prostate cancer, recent phase III placebo-controlled trials with enzalutamide, apalutamide and darolutamide all demonstrated benefits in improving metastasis-free survival. This review aims to summarize the clinical development of darolutamide, a novel next-generation androgen receptor antagonist, including preclinical data, clinical studies and the potential of darolutamide for the treatment of advanced prostate cancer. To date, darolutamide efficacy and tolerability has been demonstrated in the ARAMIS trial, which demonstrated an improvement in metastasis-free survival compared to placebo for non-metastatic castration-resistant prostate cancer patients with a rapid PSA doubling time. Ongoing studies will further evaluate the role of darolutamide in metastatic castration-sensitive prostate cancer in combination with docetaxel (ARASENS trial) and also in other stages of the disease.

Randomized phase II trial of a DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) versus GM-CSF adjuvant in patients with PSA-recurrent prostate cancer.

5037 Background: Phase I/II studies of pTVG-HP showed safety and increases in prostatic acid phosphatase (PAP)-specific T cells. Based on these, we conducted a multi-center, randomized phase II trial using pTVG-HP with GM-CSF adjuvant vs GM-CSF alone in patients with PSA-recurrent, non-metastatic, non-castrate, prostate cancer (stage M0). Methods: 99 patients with M0 prostate cancer (negative CT and bone scan) with PSA doubling time (DT) of &lt; 12m were randomly assigned to pTVG-HP + GM-CSF vs GM-CSF. Treatments were every 2 wk x 6, and then quarterly for up to 24m. Primary endpoint was 2-year MFS. Secondary endpoints included median MFS, changes in PSA DT, and immune response to PAP antigen. Additional analysis included quantitative changes in bone lesion activity by NaF PET/CT. Results: Few grade 3/4 events were observed and were not statistically different between arms. 2-year MFS between control and pTVG-HP was 42.3% and 41.8% (p = 0.97). Median MFS was not different (18.3m control versus 18.9m pTVG-HP, HR = 1.6, p = 0.13). Changes in PSA DT, and immunity to the PAP target, were not different between study arms. A pre-planned subset analysis showed median MFS was significantly longer in patients with rapid PSA DT ( &lt; 3m) treated with pTVG-HP (6.1m versus 12.0m, n = 21, HR = 4.4, p = 0.03). In patients with baseline metastases detected on NaF PET/CT, total activity (SUVtotal) increased 17% with GM-CSF alone, but decreased 29% with pTVG-HP from baseline to month 6 (n = 27, p = 0.07). Conclusions: This trial did not demonstrate an overall increase in 2-year MFS following treatment with pTVG-HP, but suggested a modest effect in patients with rapidly progressive disease. NaF PET/CT imaging suggests that pTVG-HP has a detectable effect on decreasing metastatic activity in bone. A separate trial suggests that pTVG-HP is an immune activating agent that improves activity of PD-1 blockade. A trial using pTVG-HP in combination with nivolumab in patients with M0 prostate cancer is currently underway. Clinical trial information: NCT01341652.

A retrospective observational study assessing bone metastases (mets) detection and management of patients (pts) with castration-resistant prostate cancer (CRPC) in Canada.

161 Background: Canadian Urological Association guidelines outline the scheduling of imaging modalities based on prostate-specific antigen doubling time (PSADT) to screen for mets in pts with nonmetastatic (M0) CRPC and to manage pts with metastatic (M1) CRPC. Data describing guideline adoption and real-world timing of bone scans and treatment patterns in Canadian CRPC pts are limited. Methods: A retrospective chart review conducted at 13 Canadian urology practices included pts with CRPC (PSA ≥2 ng/mL despite androgen deprivation therapy) sequentially identified in reverse chronological order starting July 30, 2015. Pts had no mets at CRPC diagnosis (index date). Data were abstracted from the index date to the chart review date. Coprimary objectives were to describe CRPC management in terms of timing of the 1st and repeat bone scans in M0 and treatment patterns when pts became metastatic. Secondary objectives described nonbone imaging. Results: 232 pts enrolled. Over the observation period 109 remained nonmetastatic (M0 cohort); 123 developed mets (M1 cohort). Median index PSADT was ~1.5x greater for the M0 cohort than the M1 cohort. 68 pts (71.6%) in M0 and 117 pts (95.1%) in M1 had ≥1 bone scan. Median (95% CI) months from CRPC diagnosis to 1st bone scan was 7.5 (5.6–9.6) for pts in M1 and 15.7 (10.0–23.0) for pts in M0. Median (95% CI) months from identification of mets to start of treatment for the M1 cohort was 3.2 (2.3–5.7). The most common therapies were abiraterone (55%) and enzalutamide (42%), with respective median (95% CI) durations of 12.7 (8.7–23.3) and 15.7 months (10.4–NE). 25% of pts received a bone-targeted agent. Conclusions: In CRPC, time to first bone scan was shorter for pts who subsequently developed mets or had rapid PSADT. Abiraterone and enzalutamide were the most common therapies in pts with mets. [Table: see text]

Metastasis-free survival as a predictor of overall survival in non-metastatic castration-resistant prostate cancer.

201 Background: Recent trials have shown that apalutamide and enzalutamide can improve metastasis free survival (MFS) in advanced non-metastatic (M0) castrate-resistant prostate cancer (CRPC). MFS is a novel clinical endpoint, demonstrated to be a strong predictor of overall survival (OS) for localized prostate cancer, yet it is unknown if this is also true for M0 CRPC. Our aim was to determine how strongly MFS in M0 CRPC correlates with OS in a real world population. Secondary analyses evaluated whether a rapid PSA-doubling time (PSADT), of ≤10 months, impacts outcomes. Methods: We performed an analysis of patients diagnosed with advanced prostate cancer, followed at the Tom Baker Cancer Centre, in Calgary, Alberta from 2001-2017. Patients were excluded if they did not develop M0 CRPC. MFS and OS were measured using the Kaplan-Meier method and the log-rank test was used to compare outcomes based on PSADT. Correlation between OS and MFS was determined using Pearson Correlation and Kendall’s Tau-B. Results: A total of 1310 patients were identified with advanced prostate cancer, of which 87 developed M0 CRPC. The median age of diagnosis of M0 CRPC was 72 years, with a median Gleason score of 7.0, initial PSA of 10.4, and PSADT of 5.1 months. Only 6 patients were treated with second-generation anti-androgens or chemotherapy. Median MFS and OS after M0 CRPC diagnosis were 44.1 and 83.7 months, respectively. Pearson Correlation between MFS and OS was strong with a coefficient of 0.850 (p &lt; 0.001); with non-parametric Kendall’s Tau, correlation was also strong with a coefficient of 0.632 (p &lt; 0.001). PSADT ≤10 months was identified in 70 patients, and associated with a significantly shorter MFS, compared to a PSADT &gt; 10 months (40.2 vs. 90.4 months; p = 0.001), as well as shorter OS (76.2 vs. 104.3 months; p = 0.008). Conclusions: MFS for M0 CRPC is strongly correlated with OS in a real world population. PSADT of ≤10 months seems to be a useful prognostic tool in estimating MFS and OS in patients with M0 CRPC. MFS was better than expected even in patients with a PSADT of ≤10 months, which may due to our adherence to the biochemical definition of castration-resistant disease, as well as lack of standard imaging intervals in the real world.

Long-term cancer control outcomes in patients with biochemical recurrence and the impact of time from radical prostatectomy to biochemical recurrence.

Rates of metastatic progression (MP) and prostate cancer mortality (PCSM) are variable after biochemical recurrence (BCR) in patients who underwent radical prostatectomy (RP). To describe long-term oncological outcomes of BCR patients and to analyze risk factors for further outcomes in these men with a special focus on RP-BCR time. We retrospectively analyzed the data of 5509 RP patients treated between 1992 and 2006. Of those, we included 1321 patients who experienced BCR (PSA level ≥0.2 ng/mL) and did not receive any neoadjuvant or adjuvant therapy. Kaplan-Meier and time dependent Cox regression models were used. Median follow-up was 121 months. MP was recorded in 177 (13.4%), PCSM in 126 (9.5%), and overall mortality (OM) in 264 (20.0%) patients. Patients with MP had worse tumor characteristics such as higher Gleason Scores (GS), rapid PSA doubling-time (DT), and shorter RP-BCR time intervals. MP-free, PCSM-free, and overall survival rates were significantly worse in patients with RP-BCR time of <12 months versus patients with 12-35.9 or ≥36 months (P ≤ 0.001). Besides higher GS and rapid PSA-DT, RP-BCR time independently predicted MP, PCSM, and OM in multivariable regression analyses. Relative to the intermediate and longest RP-BCR time interval, the shortest interval (<12) carried the highest risk for all three endpoints. Only a small proportion of BCR patients proceed to MP or PCSM. Besides higher GS and rapid PSA-DT a shorter RP-BCR interval (<12 months) heralds the most aggressive phenotype for progression to all three examined endpoints: MP, PCSM, and OM.

Phase II study of olaparib (without ADT) in men with high-risk biochemically-recurrent prostate cancer following prostatectomy, with integrated biomarker analysis.

TPS386 Background: Patients with a high-risk biochemical recurrence (BCR) of prostate cancer after local therapy, defined by a rapid PSA doubling time (≤6 mo), are likely to experience metastases and subsequently death from their disease. Early use of androgen deprivation therapy (ADT) in these patients is controversial and is associated with side effects. Non-hormonal therapies that alter the natural history of BCR disease are needed. Olaparib is a PARP inhibitor that produces responses in some men with advanced prostate cancer, particularly those with dysregulation of DNA repair genes (i.e. synthetic lethality). Preclinical data support the activity of olaparib in prostate cancer beyond the DNA repair-deficient subset, yet the optimal biomarker for treatment selection is unknown. We hypothesized that olaparib monotherapy would show activity in men with high risk BCR and sought to further define the optimal patient population for olaparib in this setting. Methods: In this investigator-initiated multi-center open-label study, eligible patients will have non-metastatic BCR after prostatectomy, with a PSA doubling time of ≤6 mo. Prior limited ADT is allowed, but testosterone must have recovered (≥150 ng/dL). Patients will receive 300mg olaparib twice daily, with disease evaluation by PSA monthly and radiographic studies every 6 mo. Patients continue olaparib until evidence of metastasis or until PSA doubles from baseline, with a minimum exposure of 3 months. The primary endpoint is the rate of decline in PSA to ≥50% from baseline (PSA50 response). Secondary endpoints include safety, progression-free survival, and the rate of durable responses. Exploratory analysis will involve biomarker discovery including somatic DNA mutation analysis, RNA expression analysis, and immunohistochemistry for DNA damage markers, done on prostatectomy specimens. The study will initially enroll an all-comer (unselected) population and will then proceed via a staged-adaptive design; if futility is observed in the all-comer population at interim analyses, enrichment with biomarker-selected patients will occur. Clinical trial information: NCT03047135.

Second-Line Hormonal Therapy for Men With Chemotherapy-Naïve, Castration-Resistant Prostate Cancer: American Society of Clinical Oncology Provisional Clinical Opinion.

Purpose ASCO provisional clinical opinions (PCOs) offer direction to the ASCO membership after publication or presentation of potential practice-changing data. This PCO addresses second-line hormonal therapy for chemotherapy-naïve men with castration-resistant prostate cancer (CRPC) who range from being asymptomatic with only biochemical evidence of CRPC to having documented metastases but minimal symptoms. Clinical Context The treatment goal for CRPC is palliation. Despite resistance to initial androgen deprivation therapy, most men respond to second-line hormonal therapies. However, guidelines have neither addressed second-line hormonal therapy for nonmetastatic CRPC nor provided specific guidance with regard to the chemotherapy-naïve population. Recent Data Six phase III randomized controlled trials and expert consensus opinion inform this PCO. Provisional Clinical Opinion For men with CRPC, a castrate state should be maintained indefinitely. Second-line hormonal therapy (eg, antiandrogens, CYP17 inhibitors) may be considered in patients with nonmetastatic CRPC at high risk for metastatic disease (rapid prostate-specific antigen doubling time or velocity) but otherwise is not suggested. In patients with radiographic evidence of metastases and minimal symptoms, enzalutamide or abiraterone plus prednisone should be offered after discussion with patients about potential harms, benefits, costs, and patient preferences. Radium-223 and sipuleucel-T also are options. No evidence provides guidance about the optimal order of hormonal therapies for CRPC beyond second-line treatment. Prostate-specific antigen testing every 4 to 6 months is reasonable for men without metastases. Routine radiographic restaging generally is not suggested but can be considered for patients at risk for metastases or who exhibit symptoms or other evidence of progression. Additional information is available at www.asco.org/genitourinary-cancer-guidelines and www.asco.org/guidelineswiki .

807TiP - A Prospective, Multinational Observational Study of Men with Later-Stage Prostate Cancer, a New Global Study to Examine Patterns of Care and Outcomes

ABSTRACT Background: The treatment landscape for men with later-stage prostate cancer has changed dramatically over the past several years due to an increase in the understanding of the natural history of the disease and the availability of multiple new therapies. The influx of new agents has made treatment decisions for clinicians increasingly complex and little is known about how patients are treated in daily clinical practice. We report the initiation of a new observational study designed to provide insight into global treatment trends and outcomes across the treatment continuum for later stage prostate cancer. The findings of this study may inform the design of new interventional studies and the development of global best practices. Trial design: This is a prospective, multinational, longitudinal, observational study. Men are included if they have been diagnosed with prostate adenocarcinoma, provided written informed consent, belong to one of three patient subsets: (1) biochemical failure and a rapid PSA doubling time following curative-intent treatment; (2) newly diagnosed with castration-resistant disease; or (3) metastatic disease at initial presentation, and will receive active treatment at study entry. Exclusion criteria include prior treatment with systemic chemotherapy, life expectancy of Disclosure: M. De Santis: Consultant or Advisory Role: Amgen, Astellas, Bayer, Dendreon, GSK, Janssen, Novartis, OncoGenex, Pierre Fabre, Roche, Sanofi, Shionogi Honoraria: Amgen, Bayer, Dendreon, GSK, Janssen, Novartis, Pierre Fabre, Roche, Sanofi Research Funding: Pierre Fabre; M.R. Cooperberg: Consultant: Astellas, Janssen, Dendreon, Abbott Labs, Genomic Health, GenomeDx, andnMyriad Genetics; T. Pickles: Advisory Board: Amgen, Astellas Honoraria: Abbvie, Diagnostic Solutions & Results Inc, Ferring, GlaxoSmithKline, Janssen Clinical Trials or Research Support: Sanofi Aventis, Oncura; R. Curiel: Employment: Astellas. All other authors have declared no conflicts of interest.

Updated analysis of a pilot study examining the role of circulating tumor cells (CTCs) in biochemical recurrence (BR) of prostate cancer.

e15023 Background: CTCs have been used as a prognostic factor in metastatic prostate cancer. Little data exists regarding the role of CTCs in BR of prostate cancer. The primary aim of this study was to determine whether there is a correlation between the number of CTCs with prostate specific antigen (PSA) levels and PSA doubling time (PSADT) in men with BR. In addition, we wished to explore the correlation of the CTCs with clinical and laboratory factors (Gleason scores, testosterone, hemoglobin, alkaline phosphatase, BMI, imaging results). Methods: BR was defined as patients (pts) who have undergone primary treatment with prostatectomy or radiation or both, with rise to ≥ 0.2 from a prior undetectable level for prior prostatectomy or > 2 mg/dl rise from post-nadir radiotherapy. The study was powered to detect a Pearson correlation of .46 with a sample size of 36. 16 of planned accrual of 36 pts were enrolled from May to December 2010. PSADT was obtained and correlated with the CTC values, categorized as PSADT of < 3 mos, 3-14.9 mos and > 15 mos. CTCs were evaluated in 7.5 mL of peripheral blood using the CTC CellSearch test. Results: Median age for 16 patients was 71.5 (range: 57 – 91); median PSA of 1.6 ng/mL (range 0.2 – 65.8); testosterone levels of 304 ng/dL (range: 31 – 600). Gleason scores ranged from 5 to 8. Prostatectomy was the primary treatment in 9 pts, radiotherapy in 5 pts, Cyberknife in 1 pt and combined radiohormones in 1 pt. Median hemoglobin was 12.81 g/dL, BMI was 27.1 and alkaline phosphatase was 68 IU/L. PSADT varied between 2.27 to 55 months, with a median of 9.6 mos. All pts accrued had 0 CTC levels except one who had a CTC of 1 but found to have biopsy-proven isolated metastatic bony lesion, with the shortest PSADT of 2.27 and an absolute PSA level of 5.6 ng/ml. Conclusions: Most prostate cancer pts with BR have negative blood CTCs but the small sample precludes a formal assessment of the correlation of CTC levels with PSADT and PSA. However, the only pt with a positive CTC also had the most rapid PSADT out of 16 pts, raising the possibility that obtaining a positive CTC may herald onset of metastatic disease and may have utility for longitudinal follow-ups of pts with BR. Supported by IRG-08-091-01 from ACS to GWUCI.

Long-Term Risk of Clinical Progression After Biochemical Recurrence Following Radical Prostatectomy: The Impact of Time from Surgery to Recurrence

BackgroundThe natural history of biochemical recurrence (BCR) after radical retropubic prostatectomy (RRP) is variable and does not always translate into systemic progression or prostate cancer (PCa) death. ObjectiveTo evaluate long-term clinical outcomes of patients with BCR and to determine predictors of disease progression and mortality in these men. Design, setting, and participantsWe reviewed our institutional registry of 14 632 patients who underwent RRP between 1990 and 2006 to identify 2426 men with BCR (prostate-specific antigen [PSA] levels ≥0.4ng/ml) who did not receive neoadjuvant or adjuvant therapy. Median follow-up was 11.5 yr after RRP and 6.6 yr after BCR. InterventionRRP. MeasurementsPatients were grouped into quartiles according to time from RRP to BCR. Survival after BCR was estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazard regression models were used to analyze clinicopathologic variables associated with systemic progression and death from PCa. Results and limitationsMedian systemic progression-free survival (PFS) and cancer-specific survival (CSS) had not been reached after 15 yr of follow-up after BCR. Cancer-specific mortality 10 yr after BCR was 9.9%, 9.3%, 7.8%, and 4.7% for patients who experienced BCR <1.2 yr, 1.2–3.1 yr, 3.1–5.9 yr, and >5.9 yr after RRP, respectively (p=0.10). On multivariate analysis, time from RRP to BCR was not significantly associated with the risk of systemic progression (p=0.50) or cancer-specific mortality (p=0.81). Older patient age, increased pathologic Gleason score, advanced tumor stage, and rapid PSA doubling time (DT) predicted systemic progression and death from PCa. Limitations included retrospective design, varied utilization of salvage therapies, and the inclusion of few patients with positive lymph nodes. ConclusionsOnly a minority of men experience systemic progression and death from PCa following BCR. The decision to institute secondary therapies must balance the risk of disease progression with the cost and morbidity of treatment, independent of time from RRP to BCR.

Adjuvant versus salvage radiation therapy for prostate cancer and the risk of death

To investigate whether salvage radiation therapy (RT) for prostate-specific antigen (PSA) failure can provide the same result as adjuvant RT, which decreases the risk of all-cause mortality (ACM) for men with positive margins (R1), or extra-capsular or seminal vesicle extension (pT3). We studied 1638 men at Duke University who underwent radical prostatectomy for unfavourable-risk prostate cancer and whose postoperative PSA was undetectable. Cox regression was used to evaluate whether salvage vs adjuvant RT in men with a rapid (<10 months) or slow (≥10 months) PSA doubling time (DT) was associated with the risk of ACM, adjusting for adverse features (pT3, R1, Gleason score 8-10), age, preoperative PSA level, comorbidity and hormonal therapy use. Despite fewer men with two or more adverse features (61 vs 82%; P=0.016), salvage for a rapid PSA DT vs adjuvant RT increased the risk of ACM [adjusted hazard ratio (AHR)=3.42; 95% confidence interval (CI)=1.27-9.20; P=0.015]. There was no difference (AHR=1.39; 95% CI=0.50-3.90; P=0.53) in the risk of ACM among men who received salvage for a slow PSA DT or adjuvant RT. Nearly all (90%) men with a slow PSA DT had Gleason score ≤7 and the majority (59%) had at most pT3 or R1 disease. Radiation therapy after PSA failure as compared with adjuvant RT was not associated with an increased risk of ACM in men with Gleason score ≤7 and pT3R0 or pT2R1 disease.

It's time to depolarise the unhelpful PSA‐testing debate and put into practice lessons from the two major international screening trials

TO THE EDITOR: When I looked at the cover of the 5 April issue of the MJA, I feared finding another article focused on discrediting the prostate-specific antigen (PSA) test. Instead, I congratulate the authors, and the Journal, for presenting one of the rare balanced articles on this topic. Denham and colleagues called for an end to taking sides in the debate over PSA testing, and focused instead on helpful guidance. The problem is not whether PSA helps us find prostate cancer, but that we lack clinical tools for deciding which patients would benefit from aggressive treatment. However, the authors point out that there are two important tools that can help with this decision: low free to total PSA ratios, and rapid PSA doubling time (< 3 years). The PSA test is now one of the most sensitive, precise and highly standardised immunoassays in the clinical laboratory. The difficulty does not lie with the measurement but with its application. The Royal College of Pathologists of Australasia, together with the Urological Society of Australia and New Zealand, recently produced a monograph that discussed the appropriate use of the PSA test. It emphasised using age-related cut-offs for PSA levels, the free to total PSA ratio, and the calculation of PSA doubling time as modern tools to achieve optimal benefit from the test. The Australian Medicare Benefits Schedule (MBS) was changed in May 2009 (following a suggestion from the Urological Society of Australia and New Zealand) to improve utilisation of free to total PSA ratios. The Box indicates the per capita request rates of PSA testing (MBS item number 66655) and free to total PSA ratios (MBS item number 66659) from May 2009 to February 2010. Consistent with Denham et al’s observation that there are regional differences in the attitudes to prostate cancer, there is a twofold variation in PSA requesting and a sevenfold difference in free to total PSA ratio requesting across the Australian states. Furthermore, the relationship between the two tests is, if anything, inverse, suggesting that increased use of PSA testing is less commonly followed up by modern tools such as free to total PSA ratio. As a chemical pathologist, the appropriate clinical use of the PSA test has been a careerlong concern of mine. Even though the discoverer of PSA has labelled the test a public health disaster, recent “case–controlled” studies using PSA in an outdated approach (without free to total PSA ratios or doubling times) have shown a marginal benefit for screening. The indiscriminate use of PSA testing can be helpful to some but disastrous for others. Modern PSA tools may significantly improve management beyond these marginal effects. As always, the value of medical investigations lies in how intelligently we use them.

Frequency of Screening Magnetic Resonance Imaging to Detect Occult Spinal Cord Compromise and to Prevent Neurological Deficit in Metastatic Castration-resistant Prostate Cancer

Aims Neurological deficit from malignant spinal cord compression (SCC) is a major complication of metastatic castration-resistant prostate cancer (CRPC). The aims of the present study were to determine the incidence of neurological deficit in metastatic prostate cancer patients and to determine the optimal frequency of screening magnetic resonance imaging (MRI) spine required to detect clinically occult radiological SCC (rSCC). Materials and methods A retrospective analysis of the clinical data of 130 consecutive patients with CRPC, with no functional neurological deficit, who had screening MRI spine from January 2001 to May 2005, was undertaken. Patients found to have rSCC received radiotherapy. All patients were followed-up to document the incidence of neurological deficit. Results Thirty-seven (28.4%) patients had rSCC on MRI. The proportion of patients free from neurological deficit at 3, 6, 12, 18 and 24 months was 94, 80, 59 and 43%, respectively, in patients who had rSCC on initial MRI and 97.5, 89, 75 and 63%, respectively, in patients who had no rSCC. A high prostate-specific antigen (PSA) level at initial MRI ( P = 0.035) and a short PSA doubling time < 3 months ( P = 0.009) significantly predicted for neurological deficit on univariate analysis, whereas back pain ( P = 0.059), although an important predictive factor, did not attain statistical significance. On multivariate analysis, only rapid PSA doubling time (<3 months) independently predicted for future neurological deficit ( P = 0.042). Conclusion MRI spine can be used to detect asymptomatic rSCC in patients with CRPC and serial estimations are required to maintain a low incidence of clinical SCC. If serial screening MRI spine is used to detect rSCC in 90% of patients before the development of neurological signs, the optimum frequency depends on the subset of patients studied. The results of our study suggest that the optimum frequency would be every 4–6 months for patients with previous SCC, rapid or high PSA or back pain and annually for asymptomatic patients.