Prostate-specific Antigen Progression-free Survival Research Articles

Radium-223 in patients with prostate specific antigen (PSA) progression and without clinical metastases following maximal local therapy: A pilot study.

Despite the curative intent of radical prostatectomy (RP) (+/- radiotherapy (RT)), 30% of the clinically localized prostate cancer (CaP) patients will develop rising PSA (prostate specific antigen). In absence of clinical recurrence, there is a lack of effective treatment strategies in order to control the disease at its earliest (micro)metastatic stage. The aim of this study was to assess safety, tolerability, and biochemical response of off-label Radium-223 (Xofigo) treatment in CaP patients with PSA relapse following maximal local therapy. We conducted a prospective, single arm, single center open-label, pilot study with Radium-223 in CaP patients with rising PSA (>0.2 ng/ml) following RP + adjuvant/salvage RT. Negative staging with 68Ga-PSMA-11 PET/CT and whole-body MRI was mandatory at time of inclusion. Patients were eligible if they exhibited adverse clinico-pathological features predictive of significant recurrence. Safety, tolerability, biochemical progression (defined as PSA increase >50% from PSA nadir) and clinical recurrence were assessed. In total, 23 patients were screened of whom 8 patients were included is the study. Radium-223 treatment was safe with no serious treatment related adverse events. One patient developed grade 3 lymphopenia. All patients rapidly developed PSA progression (median PSA progression-free survival: 5.5 months). Eventually all patients experienced clinical recurrence (median clinical recurrence-free survival 11.0 months) of whom only 2 patients developed skeletal recurrence. Radium-223 in patients with PSA relapse following maximal local treatment without clinical metastases is safe. However, the clinical benefit of Ra-223 in this setting is doubtful as significant oncological benefit is lacking.

Treatment of patients with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) in Belgium: a real world data analysis

ABSTRACT INTRODUCTION Abiraterone acetate + prednisone (AAP) and docetaxel have proven their efficacy in the treatment of patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) in clinical trials. However, real-world data are scarce. The goal of this study is to evaluate real-world data on the efficacy and safety of these therapies in mHSPC patients. PATIENTS AND METHODS Records of 93 patients from 21 different centres were retrospectively reviewed. Primary and secondary endpoints were radiographic and PSA progression-free survival (RPFS – PSA-PFS) and cancer specific and overall survival (CSS – OS), respectively. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. Differences in oncological outcome and AEs were evaluated between three treatment groups: ADT only (N=26) – ADT + AAP (N=48) – ADT + docetaxel (N=19). Survival analysis was performed using Kaplan–Meier statistics. RESULTS Median RPFS was 13 months (95% confidence interval [CI]: 9–17) for ADT only, 21 months (95% CI: 19–23) for ADT + AAP and 12 months (95% CI: 11–14) for ADT + docetaxel (p = 0.004). The 1-year PSA-PFS, CSS and OS were 73.5%, 90.7% and 88.7%, respectively, with no significant differences between the three groups. Adverse events of grade 3 or higher were not observed more frequently. CONCLUSION Retrospective real-world data show a significantly longer RPFS for mHSPC patients treated with ADT + AAP compared to ADT only or ADT + docetaxel at short-term follow-up. This can aid in counselling of mHSPC patients in daily clinical practice.

Impact of Serum γ-Glutamyltransferase on Overall Survival in Men with Metastatic Castration-Resistant Prostate Cancer Treated with Docetaxel.

Simple Summaryγ-Glutamyltransferase (GGT) is a biomarker of oxidative stress and its elevation in the serum is linked to poor survival in various malignancies; however, reports on metastatic castration-resistant prostate cancer (mCRPC) are scarce. Moreover, the source of serum GGT in men with mCRPC is largely unknown. The aims of this study were to determine the impact of serum GGT on overall survival in men with mCRPC receiving docetaxel therapy, and to examine the association between systemic and local GGT levels using immunohistochemistry. Of note, high serum GGT was associated with adverse overall survival as were low hemoglobin and high prostate-specific antigen levels. Additionally, tissue GGT expression status in prostate specimens was moderately positively associated with serum GGT. We demonstrated that pre-therapeutic serum GGT was an independent prognosticator in men with mCRPC receiving docetaxel therapy, and that overexpression of GGT in cancer cells might be responsible for the elevation of serum GGT.Background: Reports on the prognostic significance of serum γ-glutamyltransferase (GGT) in men with metastatic castration-resistant prostate cancer (mCRPC) are limited. In addition, GGT expression status in cancer tissues has not been well characterized regardless of cancer types. Methods: This retrospective study included 107 consecutive men with mCRPC receiving docetaxel therapy. The primary endpoints were associations of serum GGT with overall survival (OS) and prostate-specific antigen (PSA) response. The secondary endpoint was an association of serum GGT with progression-free survival (PFS). Additionally, GGT expression status was immunohistochemically semi-quantified using tissue microarrays. Results: A total of 67 (63%) men died during follow-up periods (median 22.5 months for survivors). On multivariable analysis, high Log GGT was independently associated with adverse OS (HR 1.49, p = 0.006) as were low hemoglobin (HR 0.79, p = 0.002) and high PSA (HR 1.40, p < 0.001). In contrast, serum GGT was not significantly associated with PSA response or PFS. Moreover, incorporation of serum GGT into established prognostic models (i.e., Halabi and Smaletz models) increased their C-indices for predicting OS from 0.772 to 0.787 (p = 0.066) and from 0.777 to 0.785 (p = 0.118), respectively. Furthermore, there was a positive correlation between serum and tissue GGT levels (ρ = 0.53, p = 0.003). Conclusions: Serum GGT may be a prognostic biomarker in men with mCRPC receiving docetaxel therapy. GGT overexpression by prostate cancer cells appears to be responsible for the elevation of GGT in the serum.

Efficacy of Combination Chemotherapy With Docetaxel, Estramustine and Carboplatin in Men With Castration-resistant Prostate Cancer.

The efficacy of docetaxel and carboplatin with oral estramustine was evaluated in patients with castration-resistant prostate cancer. Patients were treated with intravenous docetaxel at 30 mg/m2 on days 1, 8, 15, and 22 of a 28-day cycle. Intravenous carboplatin (area under the curve, 6 mg/ml/min) was administered on day 1. Patients received oral estramustine at 626.8 mg/day throughout the treatment protocol. Patients were evaluated for response, with treatment continued until cancer progression or onset of severe adverse events. Twenty patients with castration-resistant prostate cancer were treated for a median of 3.5 cycles. Prostate-specific antigen decreased by more than 30% in 18 patients, including 14 patients with a decrease of more than 50%. Median overall survival was 11 months, prostate-specific antigen progression-free survival was 6.5 months, and radiographic progression-free survival was 7 months. Docetaxel and carboplatin with oral estramustine shows efficacy against castration-resistant prostate cancer.

Cabazitaxel activity in men with metastatic castration-resistant prostate cancer with and without DNA damage repair defects

BackgroundCabazitaxel was shown to improve overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) after abiraterone/enzalutamine and docetaxel failure, though benefit by the presence of DNA damage repair (DDR) defects is unknown. With the advent of poly(adenosine diphosphate–ribose) polymerase inhibitors (PARPi) in partially overlapping indications with cabazitaxel, we aimed to determine cabazitaxel activity in men with mCRPC according to their DDR status. MethodsThis is a retrospective multicenter study that enrolled patients with mCRPC treated with cabazitaxel who had undergone DDR tumour tissue profiling. Patients with at least one deleterious germline or somatic alterations were considered DDR positive (DDR+). Each DDR + patient has been matched with a DDR negative (DDR-) from the same institution who underwent the same test. An exploratory cohort of patients found to be DDR + by liquid biopsy was also included. Prostate specific antigen (PSA) decline≥50% (PSA50), PSA progression-free survival (PFS, PSA-PFS), radiographic PFS (rPFS), clinical PFS or radiographic PFS (c/rPFS) and OS were evaluated. ResultsAmong 190 men (95 DDR+, 95 DDR-) with tissue sequencing, PSA50 was achieved with cabazitaxel in 29/92 (32%) and 33/92 (36%) in patients with DDR+ and DDR- (P = 0.64). The median rPFS was 5.33 months [95%CI 4.34–7.04] versus 5.75 months [95%CI 4.67–7.27] (P = 0.55). The median OS was 15.4 months [95%CI 12.16–26.6] and 11.5 months [95%CI 9.76–14.4] (P = 0.036), respectively. No PSA50 responses on cabazitaxel were observed in BRCA1/2 patients previously treated with PARPi (n = 10). Similar outcomes with cabazitaxel were observed in the liquid biopsy cohort (n = 63 DDR+). ConclusionsOur study suggests that cabazitaxel is active in patients with mCRPC regardless of their DDR status, although its activity in men pretreated with a PARPi may be lower.

Differential Activity of PARP Inhibitors in BRCA1- Versus BRCA2-Altered Metastatic Castration-Resistant Prostate Cancer.

We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with BRCA1/2-altered mCRPC who were treated with PARP inhibitors. The primary efficacy end point was the prostate-specific antigen (PSA) response (≥ 50% PSA decline) rate. Secondary end points were PSA progression-free survival (PSA-PFS), clinical or radiographic PFS, and overall survival. We compared clinical outcomes, and other genomic characteristics, among BRCA1- versus BRCA2-altered mCRPC. A total of 123 patients (13 BRCA1 and 110 BRCA2) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2), and veliparib (n = 2). At diagnosis, 72% of patients had Gleason 8-10 disease. BRCA1 patients were more likely to have metastatic disease at presentation (69% v 37%; P = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% v 46%; P = .78) in both groups. BRCA1 patients had more monoallelic (56% v 41%; P = .49) and concurrent TP53 (55% v 36%; P = .32) mutations. PSA50 responses in BRCA1- versus BRCA2-altered patients were 23% versus 63%, respectively (P = .01). BRCA2 patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; P = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; P = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; P = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent TP53 mutation were associated with PARP inhibitor sensitivity. PARP inhibitor efficacy is diminished in BRCA1- versus BRCA2-altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent TP53 alterations in the BRCA1 group.

Efficacy, safety and prognostic factors affecting overall survival among metastatic prostate cancer patients undergoing treatment with 177Lu-PSMA-617: A single center study

BackgroundDetermining the efficacy, safety, and prognostic factors affecting overall survival (OS) among metastatic prostate cancer patients undergoing PSMA-targeted radioligand therapy (PRLT). MethodIn this retrospective study, from November 2016 and December 2019, 43 heavily pretreated (90.7% on 1st line androgen deprivation therapy (ADT), 53.5% on 2nd line ADT, 58.1% on docetaxel) metastatic prostate cancer patients with median age of 71 years (range: 51−88 years) were enrolled. Treatment cycles were repeated every 8 weeks (range: 6–12 weeks). To evaluate the biochemical response after each cycle, prostate specific antigen (PSA) levels were measured and analyzed according to the Prostate Cancer Working Group 3 (PCWG3) criteria cutoffs. Possible adverse events after therapy were retrospectively classified according to the Common Toxicity Criteria for Adverse Events (CTCAE) v.5.0. Kaplan-Meier and multivariable Cox proportional hazard regression analyses were used to identify factors associated with OS. ResultsA total of 112 cycles of PRLT with a median of 3 cycles (range: 1–6) and median administered activity per cycle of 6.29 GBq (range: 4.45–7.7 GBq) were used. PSA decline was observed in 65.1% of patients, and best PSA decline of ≥50% and ≥90% were achieved in 39.5% and 23.3% of patients, respectively. Major (grade III) anemia and thrombocytopenia occurred in 11.6% and 7% of patients, respectively. Median OS and median PSA progression-free survival were 52 and 20 weeks, respectively. In univariate analysis, baseline hemoglobin <11.2 g/dL, baseline platelets count ≥327,000/μL, PSA decline <20.94% after first cycle of therapy, Eastern Cooperative Oncology Group (ECOG) >2, baseline PSA ≥ 115 ng/mL, cumulative dose of 177Lu-PSMA <12.95 GBq, initial alkaline phosphatase ≥196.5 U/L, initial lactate dehydrogenase ≥380 U/L and superscan pattern in bone scintigraphy were associated with worse OS. In multivariable Cox regression analysis, higher baseline platelet count, lower baseline hemoglobin, superscan pattern, and lower cumulative dose of 177Lu-PSMA remained significant predictors of poor OS. ConclusionPRLT with 177Lu-PSMA is well-tolerated and effective in metastatic prostate cancer patients who have no other treatment options available. The novel prognostic markers found in this study (high platelet count, superscan pattern) were associated with poor overall survival.

177 Lu-PSMA-617 radioligand therapy of metastatic castration-resistant prostate cancer: Initial 254-patient results from a prospective registry (REALITY Study)

PurposePreliminary data from retrospective analyses and recent data from large randomized controlled trials suggest safety and efficacy of radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC). Limited data on this modality have been published regarding large samples treated in everyday practice.MethodsWe analyzed prospectively collected registry data regarding lutetium-177 (177Lu)-PSMA-617 RLT of 254 consecutive men with mCRPC seen in everyday academic practice. Since 177Lu-PSMA-617 was experimental salvage treatment following failure of individually appropriate conventional therapies, patients were generally elderly and heavily pretreated (median age 70 years; prior taxanes 74.0%, 188/254), with late–end-stage disease (visceral metastasis in 32.7%, 83/254). Primary endpoints were response to RLT, defined by changes from baseline serum prostate-specific antigen (PSA) concentration, PSA progression-free survival (PSA-PFS), and overall survival (OS), estimated with Kaplan–Meier statistics, and caregiver-reported and patient-reported safety. Unless noted, median (minimum–maximum) values are given.ResultsPatients received 3 (1–13) 177Lu-PSMA-617 activities (6.5 [2.5–11.6] GBq/cycle) every 5.7 (3.0–11.0) weeks. Best response was ≥ 50% PSA reduction in 52.0% of patients (132/254). PSA-PFS was 5.5 (95% confidence interval [95%CI] 4.4–6.6) months and OS, 14.5 (95%CI 11.5–17.5) months. In multivariable Cox proportional-hazards modeling, response to the initial ≤ 2 RLT administrations was the strongest significant prognosticator related to OS (hazard ratio 3.7 [95%CI 2.5–5.5], p < 0.001). No RLT-related deaths or treatment discontinuations occurred; the most frequent RLT-related Grade 3/4 adverse events were anemia (18/254 patients, 7.1%), thrombocytopenia (11/254, 4.3%), and lymphopenia (7/254, 2.8%). RLT-related xerostomia, all grade 1/2, was noted in 53/254 (20.9%).ConclusionsIn a large, prospectively observed “real-world” cohort with late-stage/end-stage mCRPC and conventional treatment failure, 177Lu-PSMA-617 RLT was effective, safe, and well-tolerated. Early biochemical disease control by such therapy was associated with better OS. Prospective study earlier in the disease course may be warranted.

PD34-06 SERUM TESTOSTERONE AS A PREDICTIVE BIOMARKER FOR PSA RESPONSE: RESULTS FROM A RANDOMISED TRIAL COMPARING ENZALUTAMIDE WITH ABIRATERONE ACETATE PLUS PREDNISONE

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) III (PD34)1 Sep 2021PD34-06 SERUM TESTOSTERONE AS A PREDICTIVE BIOMARKER FOR PSA RESPONSE: RESULTS FROM A RANDOMISED TRIAL COMPARING ENZALUTAMIDE WITH ABIRATERONE ACETATE PLUS PREDNISONE Klara Kvorning Ternov, Jens Sønksen, Mikkel Fode, Henriette Lindberg, Rasmus Bisbjerg, Ganesh Palapattu, and Peter Busch Østergren Klara Kvorning TernovKlara Kvorning Ternov More articles by this author , Jens SønksenJens Sønksen More articles by this author , Mikkel FodeMikkel Fode More articles by this author , Henriette LindbergHenriette Lindberg More articles by this author , Rasmus BisbjergRasmus Bisbjerg More articles by this author , Ganesh PalapattuGanesh Palapattu More articles by this author , and Peter Busch ØstergrenPeter Busch Østergren More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002038.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Baseline serum testosterone has been suggested to be a predictive biomarker of patient important outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). Herein, we investigate the prostate-specific antigen (PSA) treatment response based on baseline testosterone levels in men treated first-line with enzalutamide (ENZ) or abiraterone acetate plus prednisone (AAP) for mCRPC. METHODS: We randomised (1:1) men to ENZ (160 mg/day) or AAP (1000 mg abiraterone acetate and 10 mg prednisone/day) groups, in this investigator-initiated phase IV trial. Eligible patients had progressive metastatic prostate cancer despite castrate levels of testosterone (<1.7nmol/L). The purpose of this trial was to compare side-effects between ENZ and AAP. In this exploratory analysis, patients were grouped according to baseline testosterone levels above the mean or less than or equal to the mean. PSA progression-free survival (PFS) was analysed with Kaplan-Meier and with univariate and multivariable (including treatment, testosterone and PSA) cox regression analyses. PSA response rates (≥50% reduction in PSA) were compared between testosterone groups with Chi-Square test for the entire cohort and treatment subgroups. Serum testosterone was measured by the gold standard assay liquid chromatography–tandem mass spectrometry. RESULTS: 166 patients (82 treated with ENZ and 84 with AAP) were included in the analyses. The mean baseline testosterone was 0.35nmol/L (10ng/dL). Median follow-up was 22.3 months. Men with baseline testosterone above the mean value had longer PSA PFS (16.6 vs. 9.9 months, hazard ratio 0.59, 95% confidence interval 0.41; 0.85, p=0.005). No interaction was found between treatment subgroups in PSA PFS (p=0.635). The PSA response rate was greater in those with higher testosterone compared with those with lower testosterone overall (91% vs 74%, p=0.007). This difference was only statistically significant in the AAP treatment subgroup (table 1). CONCLUSIONS: Baseline serum testosterone seems to be predictive of PSA response in men with mCRPC treated with ENZ or AAP and may be useful for risk stratification of men with mCRPC. Source of Funding: Herlev and Gentofte Hospital, Herlev, Denmark © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e584-e585 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Klara Kvorning Ternov More articles by this author Jens Sønksen More articles by this author Mikkel Fode More articles by this author Henriette Lindberg More articles by this author Rasmus Bisbjerg More articles by this author Ganesh Palapattu More articles by this author Peter Busch Østergren More articles by this author Expand All Advertisement Loading ...

MP60-02 TRANSCRIPTOMICS CAN PREDICT HOMOLOGOUS RECOMBINATION DEFICIENCY IN PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Markers (MP60)1 Sep 2021MP60-02 TRANSCRIPTOMICS CAN PREDICT HOMOLOGOUS RECOMBINATION DEFICIENCY IN PROSTATE CANCER Adam Weiner, Yang Liu, Matthew McFarlane, Pushpinder Bawa, Eric Li, Xin Zhao, Ziwen Li, Tanya Hammoud, Munna Hazime, R. Jeffrey Karnes, Elai Davicioni, Zachery Reichert, Arul Chinnaiyan, Tamara Lotan, and Edward Schaeffer Adam WeinerAdam Weiner More articles by this author , Yang LiuYang Liu More articles by this author , Matthew McFarlaneMatthew McFarlane More articles by this author , Pushpinder BawaPushpinder Bawa More articles by this author , Eric LiEric Li More articles by this author , Xin ZhaoXin Zhao More articles by this author , Ziwen LiZiwen Li More articles by this author , Tanya HammoudTanya Hammoud More articles by this author , Munna HazimeMunna Hazime More articles by this author , R. Jeffrey KarnesR. Jeffrey Karnes More articles by this author , Elai DavicioniElai Davicioni More articles by this author , Zachery ReichertZachery Reichert More articles by this author , Arul ChinnaiyanArul Chinnaiyan More articles by this author , Tamara LotanTamara Lotan More articles by this author , and Edward SchaefferEdward Schaeffer More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002095.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Tumors with mutations associated with homologous recombination deficiency (HRD) are uncommon in prostate cancer (PCa) and variably responsive to PARP inhibition. To better identify tumors with HRD, we developed and validated a transcriptomic signature for HRD in PCa (HRD-P). METHODS: By using an established mutational signature for tumor HRD, we created and validated a 16-gene signature for HRD-P in six independent PCa cohorts (primary PCa, n=8,224; metastatic castrate-resistant PCa [mCRPC], n=328). Molecular and clinical features were compared between HRD-P+ tumors and those with single HR-gene mutations that would have qualified patients for recent PARP inhibitor trials for mCRPC. RESULTS: HRD-P+ tumors were more numerous than tumors with single HR-gene mutations in primary (201/491, 41% vs 32/491 6.5%; Figure 1) and mCRPC (126/328, 38% vs 82/328, 25%) cases and HRD-P+ was more predictive of genomic instability suggestive of HRD. HRD-P+ was associated with shorter time to recurrence following surgery and shorter overall survival in men with mCRPC (Figure 2). In a prospective trial of mCRPC treated with olaparib (n=10), all three men with HRD-P+ experienced prolonged (>330 days) PSA progression-free survival. CONCLUSIONS: These results suggest transcriptomics can identify more patients that harbor phenotypic HRD than single HR-gene mutations and support further exploration of transcriptionally defined HRD tumors perhaps in conjunction with genomic markers for therapeutic application. Source of Funding: This work was supported in part by the National Institutes of Health grant 5U01CA196390 (EMS), the Prostate Cancer Foundation (EMS), Department of Defense grant W81XWH-15-1-0661 (EMS and TLL), the 2019 Urology Care Foundation Residency Research Award Program and the Russell Scott, Jr., MD Urology Research Fund (ABW), as well as the University of Michigan Prostate Specialized Program of Research Excellence (SPORE) P50 CA186786-05 and the Early Detection Research Network grant UO1 CA111275 (AMC). © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1041-e1041 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Adam Weiner More articles by this author Yang Liu More articles by this author Matthew McFarlane More articles by this author Pushpinder Bawa More articles by this author Eric Li More articles by this author Xin Zhao More articles by this author Ziwen Li More articles by this author Tanya Hammoud More articles by this author Munna Hazime More articles by this author R. Jeffrey Karnes More articles by this author Elai Davicioni More articles by this author Zachery Reichert More articles by this author Arul Chinnaiyan More articles by this author Tamara Lotan More articles by this author Edward Schaeffer More articles by this author Expand All Advertisement Loading ...

The heterogeneity of intraductal carcinoma of the prostate is associated with different efficacy of standard first-line therapy for patients with metastatic castration-resistant prostate cancer.

BackgroundTo explore whether metastatic castration‐resistant prostate cancer (mCRPC) patients with distinct intraductal carcinoma of the prostate (IDC‐P) subtypes respond differently to abiraterone and docetaxel treatment.MethodsWe retrospectively analyzed data of 170 mCRPC patients receiving abiraterone or docetaxel as first‐line therapy. PSA response, PSA progression‐free survival (PSA‐PFS), radiographic progression‐free survival (rPFS), and overall survival (OS) were analyzed based on the presence of IDC‐P and its subpatterns.ResultsIDC‐P was confirmed in 91/170 (53.5%) patients. Among them 36/91 (39.6%) and 55/91 (60.4%) harbored IDC‐P patterns 1 and 2, respectively. Patients with IDC‐P pattern 1 shared similar clinical outcomes to those without IDC‐P in both abiraterone and docetaxel treatment. However, against cases without IDC‐P or with IDC‐P pattern 1, patients with IDC‐P pattern 2 had markedly poorer prognosis in either abiraterone (mPSA‐PFS: 11.9 vs. 11.1 vs. 6.1 months, p < 0.001; mrPFS: 18.9 vs. 19.4 vs. 9.6 months, p < 0.001) or docetaxel (mPSA‐PFS: 6.2 vs. 6.6 vs. 3.0 months, p < 0.001; mrPFS: 15.1 vs. 12.6 vs. 5.5 months, p < 0.001) treatment. For patients without IDC‐P, docetaxel had comparable therapeutic efficacy with abiraterone. However, the efficacy of docetaxel was significantly inferior to abiraterone in patients with either IDC‐P pattern 1 (mPSA‐PFS: 6.6 vs. 11.1 months, p = 0.021; mrPFS: 12.6 vs. 19.4 months, p = 0.027) or pattern 2 (mPSA‐PFS: 3.0 vs. 6.1 months, p = 0.003; mrPFS: 5.5 vs. 9.6 months, p = 0.007).ConclusionCompared to docetaxel, abiraterone exhibited better efficacy in patients with IDC‐P of either pattern. However, IDC‐P pattern 2 responded unsatisfactorily to either abiraterone or docetaxel therapy. Novel therapeutic strategies for IDC‐P pattern 2 need further investigations.

Overexpression of CXCR7 is a Novel Indicator for Enzalutamide Resistance in Castration-Resistant Prostate Cancer Patients.

Background To evaluate whether the overexpression of chemokine receptor-7 (CXCR7) in prostatic tissues obtained from men with Castration-Resistant Prostate Cancer (CRPC) is associated with resistance to enzalutamide (Enza). Methods Based on the inclusion criteria of CRPC in EAU guidelines, all eligible patients treated in our hospital from January 2015 to December 2019 were included. Cases underwent radical prostatectomy, docetaxel-based chemotherapy, or new endocrine therapies (including Enza or abiraterone), and cases with severe cardiopulmonary disease or other malignant tumors were excluded. After immunohistochemical staining for CXCR7 expression in prostatic biopsy tissues, all enrolled cases were divided into two groups, namely, the CXCR7-positive group and the CXCR7-negative group. And then, PSA response to Enza treatment was recorded in detail and comparatively analyzed. In addition, the Cox proportional hazard modeling and the Kaplan-Meier analysis were used to determine PSA progression-free survival (PSAP-FS) and clinical or radiographic progression-free survival (CRP-FS) in this cohort. Results A total of 79 CRPC individuals were enrolled and evaluated in this study. Median follow-up durations were 24 months (range, 12-42) in the CXCR7-positive group (n = 47) and 28.5 months (range, 12-42) in the CXCR7-negative group (n = 32). The patients with lower CXCR7 expression showed much better PSA response to Enza treatment. There was 84.4% of CXCR7- cases showing decreasing PSA response, while there were 71.4% in the CXCR7/1+ group and 31.2% in the CXCR7/2+ group, respectively. All patients in the CXCR7/3+ group showed increasing PSA response to Enza treatment. And the percentage of patients whose PSA decreased over 50% is significantly higher in the CXCR7-negative group than in the CXCR7-positive group (68.8% vs. 8.5%, P < 0.001), and the percentage of patients whose PSA decreased over 90% is also remarkably higher in the CXCR7-negative group (43.8% vs. 0, P < 0.001). The Kaplan-Meier analysis demonstrated that the oncologic outcomes of CXCR7-negative patients were improved much significantly by Enza treatment in comparison with those of CXCR7-positive patients. Significantly increased median PSAP-FS (21 months vs. 6 months, P < 0.0001) and CRP-FS (27 months vs. 9 months, P < 0.0001) were obtained in the CXCR7-negative group. The further stratified analysis in all CXCR7-positive patients demonstrated that the patients with higher CXCR7 expression showed much worse outcome. The median time of PSAP-FS was 21 months in the CXCR7/1+ group, 9 months in the CXCR7/2+ group, and 6 months in the CXCR7/3+ group, while the median time of CRP-FS was 21 months in the CXCR7/1+ group, 12 months in the CXCR7/2+ group, and 6 months in the CXCR7/3+ group, respectively. Conclusion Overexpression of CXCR7 induced by an AR antagonist in CRPC patients displays much better treatment response to Enza. CXCR7 might be a novel therapeutic target gene for CRPC patients.

Prognostic Score and Benefit from Abiraterone in First-line Metastatic, Castration-resistant Prostate Cancer

BackgroundMost available prognostic nomograms in metastatic castration-resistant prostate cancer (mCRPC) are derived from datasets not representative of the current treatment landscape. A prognostic nomogram for first-line mCRPC treatment was developed from patients treated in the PREVAIL study. ObjectiveTo validate the Armstrong model in the COU-AA-302 trial. Design, setting, and participantsA post hoc analysis of mCRPC patients treated in the COU-AA-302 trial was carried out (NCT00887198). Outcome measurements and statistical analysisThe Armstrong prognostic model was applied to patients treated in COU-AA-302. A continuous risk score was derived from coefficients from the original model. Time-dependent area under the curve (tAUC) was used to evaluate the overall predictive ability of the model. Patients were categorized according to the number of risk factors present into those at a low (three or fewer risk factors), intermediate (four to six risk factors), and high (seven to ten risk factors) risk. The association with survival was assessed with Cox regression models. Interaction tests were used to assess the impact of treatment arm in each of the prognostic groups. Results and limitationsA total of 1088 patients were analyzed. The risk score was associated with overall survival (OS; tAUC 0.733). Most patients were at a low (49%) or intermediate (41%) risk. Risk category was significantly associated with OS (hazard ratio [HR]: 2.3; 95% confidence interval [CI]: 1.9–2.4; p < 0.001), radiographic progression-free survival (rPFS; HR: 1.7; 95% CI: 1.5–1.8; p < 0.001), and prostate-specific antigen progression-free survival (HR: 1.7; 95% CI: 1.5–1.9; p < 0.001). A significant interaction between risk group and OS (p = 0.007) and rPFS (p = 0.009) was observed. Survival was superior in low-risk patients (HR: 0.73; 95% CI: 0.59–0.89; p = 0.009), but similar in intermediate-risk (HR: 0.97; 95% CI: 0.79–1.21; p = 0.9) and high-risk (HR: 1.35; 95% CI: 0.80–2.28; p = 0.5) patients. Two-year OS rates in abiraterone versus placebo were 82% versus 74% in low-risk, 55% versus 52% in intermediate-risk, and 28% versus 31% in high-risk patients. ConclusionsWe validate the prognostic value of the Armstrong risk model in patients treated with first-line androgen receptor signaling inhibitors. Abiraterone provided a greater benefit in low-risk patients with less aggressive disease. Further research is needed to establish the role of Armstrong risk groups for treatment selection in mCRPC patients. Patient summaryIn this report, we validated the Armstrong nomogram in the COU-AA-302 trial population. We found a similar prognostic performance to that of the original model. Good-risk patients received the greatest benefit from abiraterone.

Prognostic significance of third-line treatment for patients with metastatic castration-resistant prostate cancer: comparative assessments between cabazitaxel and other agents.

Cabazitaxel has played an important role in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC); however, several types of sequential therapy against mCRPC have been performed in routine clinical practice. The objective of this study was to investigate the impact of third-line treatment on prognostic outcomes of mCRPC patients. This study retrospectively analyzed the clinical outcomes of 166 patients who received 3 agents following the diagnosis of mCRPC, consisting of 81 sequentially treated with either abiraterone or enzalutamide and then docetaxel, followed by third-line cabazitaxel (group A) and 85 treated with 3 agents, including abiraterone, enzalutamide, and docetaxel (group B). There were no significant differences in major characteristics at the introduction of the third-line agent between these 2 groups. The proportion of patients with prostate-specific antigen (PSA) reduction > 50% by cabazitaxel in group A was significantly greater than that by either third-line agent in group B. Both PSA progression-free survival (PFS) and overall survival (OS) following third-line therapy in group A were significantly longer than those in group B. Furthermore, OS after the diagnosis of mCRPC in group A was significantly longer than that in group B. Multivariate analysis identified independent predictors of favorable prognostic outcomes after third-line therapy as follows: high-performance status (PS), low PSA level and third-line cabazitaxel for PSA PFS, and high PS, low lactate dehydrogenase level and third-line cabazitaxel for OS. The introduction of cabazitaxel as a third-line agent could markedly improve the prognostic outcomes of mCRPC patients.

A transcriptomic model for homologous recombination deficiency in prostate cancer.

Tumors with mutations associated with homologous recombination deficiency (HRD) are uncommon in prostate cancer (PCa) and variably responsive to PARP inhibition. To better identify tumors with HRD, we developed a transcriptomic signature for HRD in PCa (HRD-P). By using an established mutational signature, we created and validated HRD-P in six independent PCa cohorts (primary PCa, n = 8224; metastatic castration-resistant PCa [mCRPC], n = 328). Molecular and clinical features were compared between HRD-P+ tumors and those with single HR-gene mutations. HRD-P+ tumors were more common than tumors with single HR-gene mutations in primary (201/491, 41% vs 32/491 6.5%) and mCRPC (126/328, 38% vs 82/328, 25%) cases, and HRD-P+ was more predictive of genomic instability suggestive of HRD. HRD-P+ was associated with a shorter time to recurrence following surgery and shorter overall survival in men with mCRPC. In a prospective trial of mCRPC treated with olaparib (n = 10), all three men with HRD-P+ experienced prolonged (>330 days) PSA progression-free survival. These results suggest transcriptomics can identify more patients that harbor phenotypic HRD than single HR-gene mutations and support further exploration of transcriptionally defined HRD tumors perhaps in conjunction with genomic markers for therapeutic application.

Prospective Evaluation of Clinical Outcomes Using a Multiplex Liquid Biopsy Targeting Diverse Resistance Mechanisms in Metastatic Prostate Cancer.

PURPOSENearly all men with prostate cancer treated with androgen receptor (AR) signaling inhibitors (ARSIs) develop resistance via diverse mechanisms including constitutive activation of the AR pathway, driven by AR genomic structural alterations, expression of AR splice variants (AR-Vs), or loss of AR dependence and lineage plasticity termed neuroendocrine prostate cancer. Understanding these de novo acquired ARSI resistance mechanisms is critical for optimizing therapy.MATERIALS AND METHODSA novel liquid biopsy technology was used to collect mRNA from circulating tumor cells (CTCs) to measure expression of AR-Vs, AR targets, and neuroendocrine prostate cancer markers. An institutional review board–approved prospective cohort (N = 99) was used to identify patterns of gene expression. Two prospective multicenter phase II clinical trials of ARSIs for men with castration-resistant prostate cancer (ClinicalTrials.gov: NCT01942837 [enzalutamide, N = 21] and NCT02025010 [abiraterone, N = 27]) were used to further validate these findings.RESULTSHierarchical clustering of CTC transcripts identified two distinct clusters. Cluster 2 (C2) exhibited increased expression of AR-regulated genes and was associated with worse overall survival (median 8.6 v 22.4 months; P < .01; hazard ratio [HR] = 3.45 [1.9 to 6.14]). In multivariable analysis, C2 was prognostic independent of other clinicopathologic variables. AR-V status was not significant when accounting for C2. Upon further validation in pooled multicenter phase II trials, C2 was associated with worse overall survival (15.2 months v not reached; P < .01; HR = 8.43 [2.74 to 25.92]), prostate-specific antigen progression-free survival (3.6 v 12 months; P < .01; HR = 4.64 [1.53 to 14.11]), and radiographic progression-free survival (2.7 v 40.6 months; P < .01; HR = 4.64 [1.82 to 17.41]).CONCLUSIONWe demonstrate that a transcriptional profile detectable in CTCs obtained from liquid biopsies can serve as an independent prognostic marker beyond AR-V7 in patients with metastatic prostate cancer and can be used to identify the emergence of multiple ARSI resistance mechanisms. This is currently being investigated in additional prospective trials.

Patient-Reported and Oncological Outcomes of Salvage Therapies for PSMA-Positive Nodal Recurrent Prostate Cancer: Real-Life Experiences and Implications for Future Trial Design.

IntroductionThe role of salvage lymph node dissection (SLND) and radiotherapy (SLNRT) in the management of nodal-only recurrent prostate cancer (PC) remains controversial. In addition, impact on health-related quality of life (HRQOL) has not been adequately evaluated yet.Materials and MethodsAnalysis was limited to patients that were diagnosed with nodal-only recurrent PC via PSMA-PET/CT. SLND was performed via open approach. For SLNRT, dose regimens were normo- or slightly hypo-fractionated with a simultaneous boost to the PET-positive recurrences. EORTC QLQ-C30 and PR-25 questionnaires were used to assess HRQOL. Continence status was assessed using daily pad usage and the validated ICIQ-SF questionnaire. For multivariable analysis, Cox regression models were used (p<0.05).Results138 patients (SLND: 71; SLNRT: 67) were included in the retrospective analysis. Median follow-up was 47 months (mo) for SLNRT patients (IQR 40–61), and 33mo for SLND patients (IQR 20–49; p<0.001). In total, 61 patients (91.0%) in the SLNRT cohort and 43 patients (65.2%; p<0.001) in the SLND cohort underwent ADT anytime during the follow-up period. In multivariate Cox regression analysis, SLNRT could be confirmed as an independent predictor for increased PSA progression-free survival (PFS; HR 0.08, 95%CI 0.040 – 0.142, p<0.001). Estimated median metastasis-free survival (MFS) was 70mo for the total cohort without statistically significant differences between both subgroups (p=0.216). There were no significant differences regarding general HRQOL, daily pad usage, and ICIQ-SF scores between the respective cohorts.ConclusionsIn a large contemporary series of patients with nodal-only recurrent PC based on PSMA-PET/CT staging, we observed significantly increased PSA PFS in patients undergoing SLNRT while no significant differences could be observed in MFS, and functional outcomes including HRQOL.

Real-World Data on Outcomes in Metastatic Castrate-Resistant Prostate Cancer Patients Treated With Abiraterone or Enzalutamide: A Regional Experience.

BackgroundBoth abiraterone and enzalutamide have shown to improve overall survival (OS), progression-free survival (PFS) and prostate-specific antigen (PSA) response in patients with metastatic castration-resistant prostate cancer (mCRPC) regardless of previous treatment with chemotherapy (COU-AA3011, COU-AA3022, AFFIRM3 and PREVAIL4). The data regarding the impact of these treatments in the real world setting is scarce. This study assessed the real world survival and disease outcomes in mCRPC patients in a regional health service in Victoria with the use of abiraterone and enzalutamide.MethodsThis retrospective clinical audit included 75 patients with diagnosis of mCRPC treated with either abiraterone or enzalutamide between January 1, 2014, and December 31, 2019, at Goulburn Valley Health. Patients were stratified according to the drug received, Eastern Cooperative Oncology Group (ECOG) performance status, Gleason score, burden of disease at diagnosis, presence of visceral metastases and use of previous chemotherapy. The primary end point was PSA response (defined as a reduction in the PSA level from baseline by 50% or more). The secondary outcomes were PSA PFS, radiographic PFS, and OS.ResultsThirty-seven patients received enzalutamide, and the other 38 received abiraterone. Only 20% of patients in either group had visceral metastases. 32% of patients receiving enzalutamide had a high burden of disease, compared to 53% receiving abiraterone. 38% of patients in the enzalutamide group and 53% in the abiraterone group had received prior chemotherapy. PSA response rates were higher in the enzalutamide group than abiraterone group (70.3% vs 37.8%). Both PSA and radiographic PFS were longer in the enzalutamide group than abiraterone group; 7 months vs 5 months for both end points. OS was also found to be longer in patients receiving enzalutamide; 30 months compared to only 13 months in patients receiving abiraterone.ConclusionBoth abiraterone and enzalutamide have shown to result in significant PSA response rates, as well as PFS and OS benefit in mCRPC patients in the real world setting. The difference in responses and survival benefit are probably impacted by the unbalanced burden of disease.

Serum and hematologic responses after three cycles of cabazitaxel therapy as predictors of survival in castration-resistant prostate cancer.

In this study, we investigated the association between the early response of serum and hematological variables and the outcome of cabazitaxel therapy. The medical records of 59 consecutive patients who had previously received docetaxel chemotherapy for the treatment of metastatic castration-resistant prostate cancer (CRPC) and who received cabazitaxel at our hospital between January 2011 and March 2020 were retrospectively reviewed and statistically analyzed. The median follow-up period after cabazitaxel initiation was 15.2months. The 30% prostate-specific antigen (PSA) response rate, median PSA progression-free survival period, and overall survival (OS) period were 45.8%, 4.3months, and 22.6months, respectively. Within 1 to 2 cycles of cabazitaxel, we were unable to identify hematological or serum kinetics that had a relationship with OS. Analysis of the variables after 3 cycles of cabazitaxel, however, revealed two factors, PSA decline > 30% (p = 0.016) and neutrophil-lymphocyte ratio (NLR) decline > 30% (p = 0.044), as the predictors of favorable outcome for OS. We established a prognostic model for predicting the OS period composed of these two factors, which exhibited distinctly separated OS curves (p = 0.004). The C-index of a model incorporating these two factors was 0.703. This is the first study to demonstrate that PSA and NLR decline 3 cycles after the initiation of cabazitaxel were associated with favorable outcome in patients with CRPC. Also, 3 cycles of cabazitaxel might be necessary to assess the efficacy of cabazitaxel therapy.

Circulating tumor DNA fraction (ctDNA%) to independently predict for clinical outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

5049 Background: CtDNA% (the tumour-derived proportion of cell-free DNA (cfDNA)) is abundant in &gt;60% of mCRPC pts and associates with adverse clinical prognostic factors. However, prognostic associations have not been comprehensively tested across clinical contexts. We evaluated the utility of ctDNA% as an independent prognostic biomarker in patients with mCRPC prior to first-line (1L) therapy. Methods: 410 treatment-naïve mCRPC pts had blood samples drawn prior to 1L therapy and followed prospectively for outcomes. Plasma cfDNA was subjected to deep targeted sequencing and ctDNA% was calculated using validated methods ( Annala, Cancer Discov, 2018 ). Overall survival (OS), PSA progression free survival (PSA PFS) and PSA declines ≥50% from baseline (PSA50 response rate (RR)) were stratified by ctDNA% and compared using Kaplan-Meier and Cox proportional hazards analysis. Results: Median age was 73 yrs. (range 45-98), the majority of pts had ECOG PS 0-1 (78%) and 9.5% had liver metastases at baseline. The most common 1L therapy employed was androgen receptor pathway inhibitors (90%). Median follow-up was 21 mo. (range 1-75) and median ctDNA% was 4.9% (range: 0-89%). Stratifying patients into high ctDNA (&gt;30%) and Low ctDNA (≤2%) groups showed stronger association with OS and PSA PFS than grouping by median (Table). In a univariate comparison to pts with low ctDNA (≤2%), pts with high ctDNA% (&gt;30%) had significantly shorter median PSA PFS, median OS and a lower PSA50 RR (Table). In a multivariable adjustment for clinical prognostic factors and cfDNA concentration, high ctDNA% remained strongly associated with OS (HR= 3.3, 95%CI: 2.1-5.3, p&lt;0.001) and PSA PFS (HR: 3.7, 95%CI: 2.4-5.9, p&lt;0.001). Although ctDNA% and total cfDNA concentration were correlated (R2=0.55), association with OS was stronger for ctDNA% than cfDNA concentration (stratified at median; HR: 2.9 (2.3-3.7), p&lt;0.001 vs HR: 2.1 (1.7-2.6), p&lt;0.001). Conclusions: In a large cohort of treatment-naïve mCRPC pts, ctDNA% prior to 1L treatment provided strong prognostic information independent of known clinical factors. These data further demonstrate the multipronged clinical utility of ctDNA-based profiling for actionable genomic alterations.[Table: see text]