PSA Doubling Time Research Articles

A Prospective Trial of 68Ga-PSMA and 18F-FDG PET/CT in Nonmetastatic Prostate Cancer Patients with an Early PSA Progression During Castration.

Tumor heterogeneity and burden, which impact treatment outcome in prostate cancer, are rarely evaluated using next-generation imaging. The trial prospectively included 37 patients who had an early PSA progression (≤2 ng/mL) during castration and high-risk (PSA doubling time ≤10 months) nonmetastatic disease by conventional imaging. All patients underwent both 68Ga-PSMA and 18F-FDG PET/CT. Lesions were classified into PSMA+FDG± lesions and PSMA-FDG+ lesions. The primary endpoint was the prevalence of PSMA-FDG+ disease. Tumor burden, predictors for positive imaging, and suitability for oligometastases-directed therapy (OMDT) were also evaluated. All patients were treated with RP and the median duration of castration was 23 months. The median PSA at imaging was 0.57 ng/mL. Overall, 114 lesions were detected in 29 of the 37 patients. A high prevalence (73%) of N+/M+ disease was observed. Of the 114 lesions, 81 were PSMA+FDG± and 33 were PSMA-FDG+. Per patient level, 9 men (24%; 95% confidence interval: 10%-39%) showed at least one new PSMA-FDG+ lesions. A short PSA doubling time (P = 0.009, OR = 8.000) was associated with PSMA+FDG± disease, while a high Gleason grade group (P = 0.022, OR = 13.091) with PSMA-FDG+ disease. Nineteen patients (51%) with 51 lesions, including 10 PSMA-FDG+ lesions, could be enrolled for OMDT. Among different disease stages, PSMA-FDG+ disease was rarely detected in the hormone-sensitive cohort, but frequently found in the castration-resistant cohort. Using 68Ga-PSMA and 18F-FDG PET, we observed a high prevalence of N+/M+ disease and a significant proportion of PSMA-FDG+ disease in patients with an early PSA progression during castration (ChiCTR1900022634).

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

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

Enzalutamide for the treatment of nonmetastatic castration-resistant prostate cancer

ABSTRACT Introduction Enzalutamide is the first characterized second-generation nonsteroidal androgen receptor inhibitor (ARi). Its efficacy has been established in several clinical trials evaluating its role in different settings of prostate cancer. Recently, enzalutamide has been approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC). Areas covered In this paper, the authors describe the chemical structure and pharmacologic characteristics of enzalutamide, providing a summary of clinical trials evaluating its efficacy and safety in prostate cancer patients. Expert opinion Enzalutamide adds to the growing arsenal of ARi used in nmCRPC. An improvement in metastasis-free survival was observed with the use of these new treatment options; recently released preliminary data report also an OS benefit. These novel agents are generally well tolerated, but their safety profiles differ slightly. Since head-to-head comparisons between ARi in nmCRPC are lacking, the adverse events profile, as well as drug availability, costs, and considerations on treatment-sequencing, would most likely influence the selection of the individual agent in this setting. Further research is needed to improve treatment selection and clarify many unsolved issues. Abbreviations ARi: nonsteroidal androgen receptor inhibitor; nmCRPC: nonmetastatic castration resistant prostate cancer; ADT: androgen deprivation therapy; OS: overall survival; PSA: prostate specific antigen; FDA: Food and Drug Administration; AR: Androgen Receptor; MFS: metastasis free survival; PSA-DT: PSA doubling time; HR: hazard ratio; CI: confidence interval; AEs: adverse events; mCRPC: metastatic castration resistant prostate cancer; mHSPC: metastatic hormone-sensitive prostate cancer; rPFS: radiographic progression-free survival; OR: odds ratio.

Predictors of survival, healthcare resource utilization, and healthcare costs in veterans with non-metastatic castration-resistant prostate cancer

ObjectivesThe objective of this study was to evaluate the association of prostate-specific antigen doubling time (PSADT) with metastasis-free survival (MFS) and overall survival (OS), and to describe healthcare resource utilization (HRU) and costs among patients with non-metastatic castrate-resistant prostate cancer (nmCRPC) in the Veterans Health Administration setting. Methods and MaterialsPatients with nmCRPC were identified from the Veterans Health Administration electronic health record database (1/2007–8/2017). PSADT was categorized as <3 months, 3 to 9 months, 9 to 15 months, ≥15 months, and unknown. MFS and OS were assessed using multivariable Cox proportional hazards regression, including PSADT as a predictor. HRU and costs were described per-patient-per-year (PPPY). ResultsAmong 12,083 patients in the study, shorter PSADT was associated with shorter MFS and OS (PSADT <3 months vs. PSADT ≥15 months hazard ratio [HR] [95% confidence interval (CI)] = 0.307 [0.281, 0.335] and 0.371 [0.335, 0.410], respectively). Patients who developed metastasis had a 3-fold higher risk of death compared to those without metastasis (HR [95% CI] = 2.933 [2.763, 3.113]). Mean HRU increased following the onset of nmCRPC and metastatic castrate-resistant prostate cancer (mCRPC); mean inpatient stays more than doubled (0.2 vs. 0.5 and 0.6 vs. 2.8 PPPY, respectively). Similar increases in healthcare costs were observed; pharmacy costs more than tripled following nmCRPC ($2,074 vs. $6,839 PPPY). From nmCRPC to mCRPC, large increases were observed for inpatient costs ($7,257–$61,691), emergency room costs ($844–$1,958), and pharmacy costs ($4,115–$26,279) PPPY. ConclusionsIn Veterans with nmCRPC, shorter PSADT was significantly associated with shorter MFS and OS. Onset of nmCRPC and mCRPC was associated with substantial HRU and cost increases.

Prostate cancer trajectory-map: clinical decision support system for prognosis management of radical prostatectomy.

PurposeProstate cancer has a low mortality rate and requires persistent treatment; however, treatment decisions are challenging. Because prostate cancer is complex, the outcomes warrant thorough follow-up evaluation for appropriate treatment. Electronic health records (EHRs) do not present intuitive information. This study aimed to develop a Clinical Decision Support System (CDSS) for prognosis management of radical prostatectomy.MethodsWe used data from 5,199 prostate cancer patients from three hospitals’ EHRs in South Korea, comprising laboratory results, surgery, medication, and radiation therapy. We used open source R for data preprocessing and development of web-based visualization system. We also used R for automatic calculation functionalities of two factors to visualize the data, e.g., Prostate-Specific Antigen Doubling Time (PSADT), and four Biochemical Recurrence (BCR) definitions: American Society of Therapeutic Radiology and Oncology (ASTRO), Phoenix, consecutive PSA > 0.2 ng/mL, and PSA > 0.2 ng/mL.ResultsWe developed the Prostate Cancer Trajectory Map (PCT-Map) as a CDSS for intuitive visualization of serial data of PSA, testosterone, surgery, medication, radiation therapy, BCR, and PSADT.ConclusionsThe PCT-Map comprises functionalities for BCR and PSADT and calculates and visualizes the newly added patient data automatically in a PCT-Map data format, thus optimizing the visualization of patient data and allowing clinicians to promptly access patient data to decide the appropriate treatment.

919 - Efficacy and safety of darolutamide (DARO) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and a prostate-specific antigen doubling time (PSADT) >6 months

919 - Efficacy and safety of darolutamide (DARO) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and a prostate-specific antigen doubling time (PSADT) >6 months

Detection rate, pattern of relapse and influence on therapeutic decision of PSMA PET/CT in patients affected by biochemical recurrence after radical prostatectomy, a retrospective case series.

68Ga-Prostate-specific membrane antigen (PSMA) PET/CT is widely used in patients with biochemical recurrence (BCR) after radical prostatectomy. We collected data about patients staged with PSMA PET/CT after BCR (PSA < 1ng/ml) in four different institutes. Impact of baseline features (Gleason score, risk classification, PSA at recurrence, PSA doubling time and time to recurrence) was explored to understand predictive factors of (PSMA) PET/CT positivity. Impact of restaging on following treatment approaches was reported. 92 patients were included. PSMA PET/CT detection rate was 56.5% and low-volume disease (≤ 3 non-visceral lesions) was detected in 52.2% of patients. After positive scan, 13.5% of patients still lies on observation, ADT alone was administered in 30.8% of cases, Stereotactic body RT (SBRT) alone was delivered to 44.2% of patients and 11.5% of patients underwent concomitant SBRT and ADT. Seven patients underwent conventional salvage prostate bed RT. Chi-squared test showed a higher rate of positive PSMA PET/CT for patients with Gleason score > 7 (p = 0.004) and TTR < 29.5months (p = 0.003). PSMA PET/CT showed a high detection rate. This influenced clinical management in a significant percentage of patients, allowing treatment tailoring on the basis of imaging.

Early salvage radiotherapy in patients with biochemical recurrence after radical prostatectomy: Its impact and optimal candidate.

We aimed to identify the optimal candidates for early salvage radiotherapy (SRT) among patients with biochemical recurrence (BCR) after radical prostatectomy (RP). This multi-institutional retrospective study included 371 patients treated using SRT after RP. The median (range) PSA level at BCR was 0.36 (0.10-2.00) ng/mL. The association between early SRT (ie, starting PSA level<0.50) and BCR after SRT was tested in each subgroup according to our own risk stratification. The median follow-up time was 51 months. By multivariate analysis, pT3b, Gleason score ≥ 8, negative surgical margins, PSA doubling time<6 months, and non-early SRT were associated with BCR after SRT. Patients were stratified by four risk factors other than non-early SRT: (1) low risk (0 risk factor), (2) intermediate risk (1 risk factor), and (3) high risk (≥2 risk factors). The BCR-free survival was higher in the early SRT group than the nonearly SRT group in the high-risk subgroup (P=0.020), whereas that was similar between two groups in the low-risk and intermediate-risk subgroups (P=.79 and .18, respectively). Multivariate analysis revealed that early SRT was beneficial for the high-risk subgroup (P=.032), whereas early SRT was not associated with improved outcomes in the low-risk and intermediate-risk subgroups (P=.92 and 1.0, respectively). This study suggested that early SRT seemed to contribute to better biochemical control for patients with more adverse features, whereas no benefit was observed in men with no adverse features.

Diagnostic performance of F-18 fluciclovine PET/CT in post-radical prostatectomy prostate cancer patients with rising prostate-specific antigen level ≤0.5 ng/mL.

The aim of the study was to assess the diagnostic performance of fluciclovine positron emission tomography (PET)/computerized tomography (CT) in post-radical prostatectomy prostate cancer patients with rising prostate-specific antigen (PSA) ≤0.5 ng/mL, and identify the associated predictive factors of positive studies. From 30 June 2017 to 9 August 2019, patients with post-radical prostatectomy prostate cancer who underwent F-18 fluciclovine PET/CT and had PSA level within 2-week interval (PSAPET) ≤0.5 ng/mL were enrolled into this single-institution retrospective study. Data on tumor characteristics, including Gleason scores, extra-prostatic extension, seminal vesicle invasion, surgical margin and nodal metastasis, PSA after radical prostatectomy, previous hormonal therapy, PSA doubling time (PSADT), scanner type, PSAPET and site of recurrence were collected. Comparison of these factors between groups of positive and negative fluciclovine PET/CT was done by using Mann-Whitney U-test and Fisher's exact test. Of 94 eligible patients with post-radical prostatectomy prostate cancer, 10 patients had positive studies (10.6%). Detection rate at PSAPET 0.1, 0.2, 0.3, 0.4 and 0.5 ng/mL were 0% (0/11), 0% (0/15), 20% (6/30), 4% (1/25) and 23.1% (3/13), respectively. Upon multivariate analysis of clinical factors, only a PSADT <3 months (P = 0.023) was shown to have a statistically significant correlation with a positive study. In post-radical prostatectomy prostate cancer patients with rising PSA 0.1-0.5 ng/mL, the sensitivity of F-18 fluciclovine PET/CT for identifying tumor recurrence/metastases is poor with an overall detection rate of 10.6%. Larger prospective studies are required to validate these findings.

Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer

BackgroundPreliminary trial results showed that enzalutamide significantly improved metastasis-free survival among men who had nonmetastatic, castration-resistant prostate cancer and rapidly increasing prostate-specific antigen (PSA) levels while taking androgen-deprivation therapy. Results from the final analysis of overall survival have not yet been reported.MethodsIn this double-blind, phase 3 trial, men with nonmetastatic, castration-resistant prostate cancer (defined on the basis of conventional imaging and a PSA doubling time of ≤10 months) who were continuing to receive androgen-deprivation therapy were randomly assigned (in a 2:1 ratio) to receive enzalutamide at a dose of 160 mg or placebo once daily. Overall survival was assessed with a group sequential testing procedure and an O’Brien–Fleming–type alpha-spending function.ResultsAs of October 15, 2019, a total of 288 of 933 patients (31%) in the enzalutamide group and 178 of 468 (38%) in the placebo group had died. Median overall survival was 67.0 months (95% confidence interval [CI], 64.0 to not reached) in the enzalutamide group and 56.3 months (95% CI, 54.4 to 63.0) in the placebo group (hazard ratio for death, 0.73; 95% CI, 0.61 to 0.89; P=0.001). The exposure-adjusted rate of adverse events of grade 3 or higher was 17 per 100 patient-years in the enzalutamide group and 20 per 100 patient-years in the placebo group. Adverse events in the enzalutamide group were consistent with those previously reported for enzalutamide; the most frequently reported events were fatigue and musculoskeletal events.ConclusionsEnzalutamide plus androgen-deprivation therapy resulted in longer median overall survival than placebo plus androgen-deprivation therapy among men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level. The risk of death associated with enzalutamide was 27% lower than with placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924.)

A phase II randomized trial of RAdium-223 dichloride and SABR Versus SABR for oligomEtastatic prostate caNcerS (RAVENS)

BackgroundMetastasis directed therapy (MDT) for patients with oligometastatic disease is associated with improvements in progression free survival (PFS) and overall survival (OS) compared to systemic therapy alone. Additionally, within a prostate-cancer-specific cohort, MDT is able to forestall initiation of androgen deprivation therapy (ADT) in men with hormone-sensitive, oligometastatic prostate cancer (HSOPCa) compared to observation. While MDT appears to be safe and effective in HSOPCa, a large percentage of men will eventually have disease recurrence. Patterns of failure in HSOPCa demonstrate patients tend to have recurrence in the bone following MDT, raising the question of sub-clinically-apparent osseous disease. Radium-223 dichloride is a radiopharmaceutical with structural similarity to calcium, allowing it to be taken up by bone where it emits alpha particles, and therefore might have utility in the treatment of micrometastatic osseous disease. Therefore, the primary goal of the phase II RAVENS trial is to evaluate the efficacy of MDT + radium-223 dichloride in prolonging progression free survival in men with HSOPCa.MethodsPatients with HSOPCa and 3 or less metastases with at least 1 bone metastasis will be randomized 1:1 to stereotactic ablative radiation (SABR, also known as stereotactic body radiation therapy (SBRT)) alone vs SABR + radium-223 dichloride with a minimization algorithm to balance assignment by institution, primary intervention, prior hormonal therapy, and PSA doubling time. SABR is delivered in one to five fractions and patients in the SABR + radium-223 dichloride arm will receive six infusions of radium-223 dichloride at four-week intervals. The primary end point is progression free survival. The secondary clinical endpoints include toxicity and quality of life assessments, local control at 12 months, locoregional progression, time to distant progression, time to new metastasis, and duration of response.DiscussionThe RAVENS trial will be the first described phase II, non-blinded, randomized study to compare SABR +/− radium-223 dichloride in patients with HSOPCa and 3 or less metastases with at least one bone metastasis. The primary hypothesis is that SABR + radium-223 dichloride will increase median progression-free survival from 10 months in the SABR arm to 20 months in the SABR + radium-223 dichloride arm.Trial registrationsClinicaltrials.gov. Identifier: NCT04037358. Date of Registration: July 30, 2019. Date of First Participant Enrolled: August 9, 2019. Date of Last Approved Amendment: October 16, 2019. Protocol Version: Version 5.

Surveillance active du cancer de prostate : facteurs prédictifs d’échecs après 5 ans de suivi

The objective of this work was to identify the risk factors (RFs) of active surveillance (AS) interruption in a prostate cancer (PCa) single-center retrospective cohort of patients. All patients in AS between January 2011 and October 2019 were retrospectively included in a computerized database. The group of patients who had an AS interruption was compared to the one still under AS, in order to identify potential risk factors for the interruption of the surveillance protocol. Two hundred and two patients have been included in the AS cohort with a median follow-up of 32months. At the time of analysis, 72 patients (36%) were not under the AS protocol anymore, 118 (58%) were still under AS and 12 (6%) were lost of follow-up. Sixty-six patients (92%) had left SA due to PCa progression, 4 (5%) by personal choice and 2 (3%) switched to watchful waiting. A PSA doubling Time<3years (PSADT<3years) has been identified as the only statistically significant RF for AS interruption, both in the unvaried (P<0.001) and multivariate (OR=5.403, P<0.01) analysis. It was also the only RF of AS interruption in the early analysis in the first three years of AS, in the unvaried analysis (P=0.021) and the multivariate analysis (OR=3.612, P=0.018). PSADT was the only RF of AS early and late interruption in our study. It represents a major inclusion criterion in AS protocol during the initial assessment. 3.

Efficacy of androgen receptor antagonists in combination with androgen deprivation therapy in nonmetastatic, castration-resistant prostate cancer: A systematic review and meta-analysis of published phase III randomized controlled trials.

e17606 Background: Nonmetastatic, castration-resistant prostate cancer (nmCRPC) often heralds metastatic disease which is responsible for majority of the morbidity and mortality associated with prostate cancer. Hence, delaying metastasis is an expedient therapeutic goal for the patients with nmCRPC. Three androgen receptor (AR) antagonists — apalutamide, enzalutamide, and darolutamide — have been approved recently for nmCRPC on the basis of prolongation of metastasis-free survival. The purpose of our meta-analysis is to consolidate the efficacy data of AR-antagonists prolonging metastasis-free survival in nmCRPC. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE, and meeting abstracts as per PRISMA guidelines from inception until November 2019. Phase 3 RCTs using AR-antagonists for nmCRPC were included in the final analysis. We used generic inverse variance method and random effects model to calculate the pooled hazard ratio (HR) for distant metastasis or death with 95% confidence interval (CI). Heterogeneity was tested with I2 value and Cochran’s Q test. Results: Three phase 3 RCTs (ARAMIS, PROSPER, and SPARTAN) randomizing 2694 patients in the AR-antagonist arms and 1423 patients in the control arms are included in the final analysis. All studies enrolled only patients with prostate specific antigen (PSA) doubling time of 10 months or less. AR-antagonists used in the study arms were — ARAMIS: darolutamide, PROSPER: enzalutamide, and SPARTAN: apalutamide. Placebo was used in the control arms. All patients continued androgen deprivation therapy (ADT). Randomization was 2:1 in all studies. The pooled HR for distant metastasis or death was highly significant at 0.32 (95% CI: 0.25 - 0.41; P &lt; 0.00001, I2 = 79%) in the favor of AR-antagonist arm in overall population. The pooled HR remained significant when patients were stratified according to PSA doubling time. For patients with PSA doubling time &gt; 6months, the pooled HR was 0.34 (95% CI: 0.27 - 0.43; P &lt; 0.00001, I2 = 0%); for patients with PSA doubling time ≤6 months, the pooled HR was 0.32 (95% CI: 0.25 - 0.41; P &lt; 0.00001, I2 = 73%). Conclusions: Our meta-analysis demonstrated addition of AR-antagonists to ADT significantly prolongs the metastasis-free survival in patients with nmCRPC — an exciting new development in the management of prostate cancer.

Prospective evaluation of 18F-DCFPyL PET/CT in biochemically recurrent prostate cancer: Analysis of lesion localization and distribution.

5556 Background: 18F-DCFPyL, a promising PET agent targeting prostate specific membrane antigen (PSMA), is prospectively evaluated in a single academic center for detecting recurrent lesions in prostate cancer patients with biochemical recurrence (BCR). Methods: We prospectively enrolled 150 men (51-91 years old, mean ± SD: 70.3±7.5) with biochemical recurrence (PSA median 2.38 ng/mL, range 0.12 to 698.4) after primary definitive treatment with prostatectomy (65%), radiotherapy (35%) or both (19%). The 18F-DCFPyL positive lesions compatible with prostate cancer were evaluated by two independent readers. Impact of 18F-DCFPyL PET/CT on patient management was recorded from clinical chart review. Results: 18F-DCFPyL PET/CT had an overall positivity rate of 83% (125 scans), which increased with higher prostate specific antigen (PSA) levels (ng/mL): 63% (PSA &lt; 0.5), 75% (0.5≤PSA &lt; 1), 91% (1≤PSA &lt; 2), 95% (2≤PSA &lt; 5) and 98% (PSA≥5), respectively. In the cohort who underwent prostatectomy, 18F-DCFPyL PET/CT had higher positivity rate in patients with shorter PSA doubling time (PSAdt) (94% in PSAdt 0-3 months vs. 53% in PSAdt &gt; 12 months, P&lt; 0.01). No difference of 18F-DCFPyL positivity rate was observed in post-radiation patients with different PSAdt, nor were there differences between patients with low grade (Gleason 6) or higher-grade prostate cancer (Gleason 7-10). 20 patients (13%) had lesions in the prostate bed only and 41 patients (27%) had oligometastatic disease (1-3 lesions), making them candidates for locally targeted therapy. We identified a total of 1455 18F-DCFPyL positive lesions, including 51 lesions in the prostate bed, 271 pelvic and 463 extra-pelvic lymph nodes, approximately 585 osseous lesions, including 5 patients with diffuse osseous metastases, and 85 lesions in other organs (most commonly in the lungs). 91 out of 150 patients (61%) had change in treatment after 18F-DCFPyL PET and, most noticeably, 48 of these patients (32% total) had lesions only localized on 18F-DCFPyL PET/CT despite negative conventional imaging. Conclusions: 18F-DCFPyL PET/CT holds great potential to be a “one-stop shop” diagnostic tool in the work-up of BCR prostate cancer, with high (61%) impact on the management of these patients. Clinical trial information: NCT03501940 .

Final overall survival (OS) from PROSPER: A phase III, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC).

5515 Background: PROSPER previously demonstrated a statistically significant and clinically meaningful improvement in metastasis-free survival (MFS) (hazard ratio [HR] 0.29; 95% CI 0.24-0.35; P &lt; .001) in men with nmCRPC and rapidly rising prostate-specific antigen (PSA) who received ENZA. When first reported, OS was immature with only 165 of 596 (28%) prespecified deaths. Here we report results from the final OS analysis. Methods: Men with nmCRPC, PSA doubling time ≤ 10 mo, and PSA ≥ 2 ng/mL at screening continued androgen deprivation therapy (ADT) and were randomized 2:1 to ENZA 160 mg or PBO. OS treatment effect was assessed using a group sequential testing procedure with O’Brien-Fleming-type alpha spending function ( P ≤ .021 required for statistical significance). Medians were estimated using the Kaplan-Meier method; 95% CIs using a stratified Cox regression model. Results: As of Oct 15, 2019 (median follow-up ≈ 48 mo), there were 466 deaths (288 [30.9%] and 178 [38.0%] in the ENZA and PBO arms, respectively). ENZA significantly prolonged OS compared with PBO (HR 0.73; 95% CI 0.61-0.89; P = .0011). Median OS was 67.0 mo (95% CI 64.0-not reached) in the ENZA arm and 56.3 mo (95% CI 54.4-63.0) in the PBO arm. Subsequent antineoplastic therapies were initiated after treatment discontinuation by 310 (33%) men in the ENZA arm vs 303 (65%) in the PBO arm. Median duration of treatment was 33.9 mo vs 14.2 mo with ENZA vs PBO, respectively. Grade ≥ 3 adverse events (AEs) were reported by 48% of men in the ENZA arm vs 27% in the PBO arm (16% vs 6% were drug related, respectively). AEs with event rates per 100 patient-yr that were ≥ 2 points higher with ENZA vs PBO were falls (9 vs 4), fatigue (14 vs 12), and hypertension (7 vs 5). Conclusions: ENZA treatment resulted in a statistically significant 27% reduced risk of death compared with PBO, demonstrating that initiation of ENZA + ADT before the onset of detectable metastasis improves OS in men with CRPC and rapidly rising PSA. This OS benefit ensues despite crossover from the PBO arm to ENZA and higher rates of subsequent antineoplastic therapies in men from the PBO arm. Safety was consistent with previous clinical trials. This final OS analysis from PROSPER provides prospective validation of MFS as a potential surrogate endpoint for OS in nmCRPC and supports the continued use of ENZA + ADT as a standard of care in men with nmCRPC and rapidly rising PSA. Clinical trial information: NCT02003924 .

The impact of complications after diagnostic biopsy on repeat biopsy in men: Results from the Prostate Cancer Research International: Active surveillance (PRIAS-JAPAN) study.

e17616 Background: Active surveillance(AS) is the strategy to avoid the overtreatment for favorable prostate cancer. For safer AS protocol execution, repeat protocol biopsy is essential in evaluating cancer aggressiveness accurately. However, some men on AS refuse repeat protocol biopsy because of burdens on biopsy. We aimed to assess the complications of prostate biopsy and the impact of complications after diagnostic biopsy on repeat protocol biopsy from the analysis Japanese cohort forming part of the Prostate cancer Research International: Active surveillance (PRIAS) study. Methods: PRIAS-JAPAN started in January 2010, 39 institutions are participating in this study. Men are prospectively followed and repeat protocol biopsy are planned at 1 year and 4 years thereafter, or if prostate specific antigen-doubling time is &lt; 10 years. Data was collected on the complications such as infection, hematuria, hematospermia, pain, and antibiotics, and approach of biopsy, retrospectively. We compared the complications in diagnostic biopsy between repeat biopsy acceptance group and repeat biopsy non-acceptance group at 1 year. Results: From 2010 to 2018, 862 men with low-risk prostate cancer were prospectively enrolled in PRIAS-JAPAN. 794 men (92%) actually proceeded to protocol at 1 year. Of the 794 men, repeat protocol biopsy non-acceptance rate at 1 year was 18.4%(146 men). According to differences in the complications of diagnostic biopsy, hematuria(p = 0.003) and pain(p &lt; 0.001) rate were significantly higher in repeat biopsy non-acceptance group, but infection(p = 0.105) and hematospermia(p = 0.224). Approach of biopsy(p = 0.651) was not different in two groups. Conclusions: Hematuria and pain in diagnostic biopsy were significantly more frequent in repeat biopsy non-acceptance group. Our study supports the importance of adequate explanation and management of the complications at biopsy to improve the rate of protocol biopsy acceptance. [Table: see text]

Single nucleotide polymorphisms (SNPs) as predictors of efficacy of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC).

e17582 Background: Cabazitaxel is a semi-synthetic derivative of a natural taxoid approved for the treatment of mCRPC patients (pts) after failure to docetaxel. Despite its proven efficacy, there is variability in the response, progression-free survival (PFS) and overall survival (OS) of pts. Changes in the genetic constitution of the individual such as the SNPs could explain this variability. The aim of this study was to evaluate the impact of certain SNPs in cabazitaxel activity. Methods: Clinical data from 67 mCRPC pts treated with cabazitaxel between March 2011 and October 2016 were collected. DNA was isolated from formalin fixed paraffin-embedded tumor samples. 56 SNPs in 5 genes related with metabolism and/or mechanism of action of cabazitaxel (CYP3A4, CYP3A5, ABCB1, TUBB1, CYP2C8) were chosen based on their Minor Allele Frequency, linkage disequilibrium and information from dbSNP and analyzed by TaqMan OpenArray (Lifetech). The presence/absence of mutant alleles of the selected SNPs was correlated with clinical features, progression free survival (PFS) and overall survival (OS) of prostate cancer. Chi-square test and Kaplan-Meier with log-rank test were used for statistical analyses. Results: The median age was 61 years (range 44-82). 56.7% (n = 38) had a Gleason score ≥8 and 94% had received docetaxel in first line. Type of response to cabazitaxel was associated with median OS (Partial response = 24.35 months, Stable disease = 11.16 months, Progression disease = 5.8 months; p= 0.045). Univariate analysis, showed worsed OS at 1 year for wild type status of SNP rs151352 (OR = 4, 95%CI 1.27-12.58, p= 0.029). In addition, two SNPs (rs11773597, rs1202186) were associated with radiological response to cabazitaxel ( p= 0.031 and p= 0.030 respectively). Other 7 SNPs (rs11773597, rs2235040, rs1045642, rs1419745, rs1202170, rs6949448, rs11572093) were associated ( p&lt;0.05) with Gleason score, pain, PSA doubling time, febrile neutropenia and asthenia. Conclusions: A particular SNP profile could be predictive of efficacy and related with toxicity in mCRPC population treated with cabazitaxel after progression to docetaxel. These outcomes become particularly relevant in patient selection given the recent results of the CARD trial.

Metastasis free survival in older men with nonmetastatic castration-resistant prostate cancer treated with androgen receptor inhibitors: An FDA-pooled analysis.

12038 Background: The FDA has approved three androgen receptor (AR) inhibitors for nonmetastatic castration-resistant prostate cancer (nmCRPC) based on improvements in metastasis-free survival (MFS). MFS is an earlier endpoint, defined as the time from randomization to either imaging-detectable distant disease or death. This pooled analysis examines MFS, time to initiation of cytotoxic chemotherapy (TTCyto), and safety outcomes in men over 80 treated with AR inhibitors. Methods: Data was pooled from three randomized controlled studies (n=4117) of AR inhibitors for nmCRPC. The treatment effect of AR inhibitors on MFS and TTCyto across age groups was evaluated using Kaplan-Meier estimates and a Cox proportional hazards regression model. Hazard Ratios for MFS and TTCyto were adjusted for baseline ECOG, total Gleason score, PSA doubling time, and prior bone-targeting therapy. Results: For patients age 80 years or older (n=675) who were treated with AR inhibitors, the hazard ratio was 0.38 (95% CI 0.29, 0.49) with an estimated median MFS of 40 months (95% CI 36, 41) versus 22 months (95% CI 18, 29) for those treated with placebo (n=348). For patients &lt;80 (n=2019) treated with AR inhibitors, the HR was 0.31 (95% CI 0.27, 0.36) with an estimated median MFS of 41 months (95% CI 36, NR) versus 16 months (95% CI 15, 18) for those treated with placebo (n=1075). Patients over 80 also derived similar improvements in time to initiation of cytotoxic chemotherapy (HR 0.43 95% CI 0.23, 0.82), compared to their younger counterparts (HR 0.41 95% CI 0.33, 0.50). See Table for selected safety outcomes. Conclusions: In an exploratory subgroup analysis, older men (≥80) with nmCRPC derived similar benefit in MFS and time to initiation of cytotoxic chemotherapy with AR inhibitors compared with younger patients. Men age 80 and above experienced higher rates of Grade 3-4 adverse events, serious adverse events, falls, and fractures. This trend towards increased toxicity was observed regardless of treatment arm. Analysis of patient reported outcomes is ongoing. [Table: see text]

Safety outcomes of darolutamide versus apalutamide and enzalutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC): Matching-adjusted indirect comparisons.

5561 Background: Randomized nmCRPC trials comparing darolutamide (D), apalutamide (A) and enzalutamide (E) have not been reported. Safety of these therapeutics has important implications in assessing patient risk-benefit concerns. Matching-adjusted indirect comparison (MAIC) is a method to perform indirect treatment comparisons adjusting for cross-trial heterogeneity. Objective: To compare the safety outcomes of D vs. A or E using MAIC. Methods: Data from the ARAMIS (D vs. placebo [PBO]), SPARTAN (A vs. PBO) and PROSPER (E vs. PBO) trials were used. Key safety outcomes including adverse events (AEs) that have central nervous system relevance were compared using anchored MAIC. Individual patient level data (IPD) from ARAMIS were selected and re-weighted to match the inclusion criteria and baseline characteristics published in SPARTAN and PROSPER (no access to their IPD). The Benjamini-Hochberg approach was applied to adjust for multiplicity. The D vs A MAIC matched on 7 covariates: age, prostate-specific antigen (PSA) level and doubling time, Eastern Cooperative Oncology Group (ECOG), Gleason score, bone-sparing agent use and prior surgery. Sensitivity analyses were conducted matching on different sets of covariates. D vs. E were matched on age, region, PSA level and doubling time, ECOG, Gleason score and bone-sparing agent use. Risk difference (RD) ([DARO – PBOARAMIS] – [ENZA – PBOPROSPER]) and odds ratio (OR) (ORARAMIS/ORPROSPER) were calculated. RD&lt;0 or OR&lt;1 indicate lower AE risk for D. Results: For D vs. A, the effective sample sizes (ESS) of D and its placebo (PBO) arm were 604 and 391 after matching. Fall, fracture, and rash were statistically significantly lower for D vs. A (Table). For D vs. E, the ESS of D and PBO arm were 580 and 395, respectively. Fall, dizziness, mental impairment, hypertension, fatigue and severe fatigue were statistically significantly lower for D vs. E. Conclusions: After adjusting for trial differences, D showed favorable safety profile in fall, dizziness, mental-impairment, hypertension, rash, fatigue, and fracture. [Table: see text]

Final survival results from SPARTAN, a phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC).

5516 Background: SPARTAN evaluated APA vs PBO in pts with nmCRPC and a prostate-specific antigen doubling time of ≤ 10 mo receiving androgen deprivation therapy (ADT). At primary end point analysis of metastasis-free survival (MFS), APA significantly improved median MFS by 2 yrs, as well as time to metastasis, progression-free survival, and time to symptomatic progression vs PBO (Smith, et al. NEJM 2018); overall survival (OS) results were immature. SPARTAN was unblinded upon meeting the primary end point; pts still on PBO were allowed to cross over to APA. Final survival results are reported herein. Methods: 1207 nmCRPC pts were randomized 2:1 to APA (240 mg QD) or PBO plus ongoing ADT. At progression, pts could receive open-label sponsor-provided abiraterone acetate + prednisone. After the primary efficacy end point (MFS) was met, 76 PBO pts (19%) crossed over to APA. OS and time to cytotoxic chemotherapy (TTCx) were tested by group sequential testing procedure with O’Brien-Fleming (OBF)-type alpha spending function. Time-to-event end points were analyzed by Kaplan-Meier method and Cox model. A sensitivity analysis for OS, accounting for crossover using a naïve censoring approach, was conducted. Results: With follow-up of 52.0 mo, 428 (of 427 required) OS events had occurred. Median treatment duration: APA, 32.9 mo; PBO, 11.5 mo. Median OS was significantly longer with APA + ADT vs PBO + ADT (73.9 vs 59.9 mo), (hazard ratio [HR], 0.784, Table). APA significantly lengthened TTCx (HR, 0.629). Discontinuation rates (APA vs PBO) due to progressive disease were 42.7% vs 73.9%, and due to adverse events (AE) 15.2% vs 8.4%. Safety was consistent with previous reports; grade 3/4 treatment-emergent (TE) AEs of special interest were rash 5.2%, fractures 4.9%, falls 2.7%, ischemic heart disease 2.6%, hypothyroidism 0%, and seizures 0%. 1 TEAE leading to death (myocardial infarction) was considered potentially APA related. Conclusions: In pts with nmCRPC, APA + ADT significantly improved OS compared with PBO + ADT, with median OS &gt; 6 yr in the APA + ADT group and 14 mo improvement over PBO + ADT. Benefit from APA was observed despite a 19% crossover from PBO. The safety profile of APA was consistent with prior interim analyses. Clinical trial information: NCT01946204 . [Table: see text]