PSA Doubling Time Research Articles

Real world prospective evaluation of clinical outcomes in patients with non-metastatic castrate resistant prostate cancer treated with darolutamide.

335 Background: The RECORD Study is a real world data, prospective evaluation of clinical outcomes in patients with nmCRPC treated with Darolutamide. This study will increase the understanding of treatment response and management and in particular inform regarding use of next generation imaging in this setting. Methods: Patient data from 9 UK centres was collected based on the recommendation of NICE for Darolutamide as an option for the treatment of non-metastatic castrate resistant prostate cancer (nmCRPC) from November 2020. Data cut-off was 15 September 2022. The study is ongoing. Results: 87 patients were analysed with a median age of 78 (range 61-92). Median pre-treatment PSA and PSA doubling time (PSAdT) were 13 (range 1.99-110.6) mg/L and 5.05 (range 0.6 - 10) months. 42 patients (49.4%) had pre-treatment PSAdT of <6 months and 43 (50.6%) patients had PSAdT of ≥6 months (2 patients had no pre-treatment PSAdT data). 6 patients (6.90%) had next generation imaging prior to initiation of Darolutamide. Median duration of treatment on Darolutamide was 17 months for patients with pre-treatment PSAdT <6 months but median duration had not been reached for patients with pre-treatment PSAdT ≥6 months after 24 months of treatment, a significant difference p=0.018 (HR=0.385, 95% CI 0.17-0.88). 30 patients have come off treatment so far (34.5%); 21 (70%) for disease progression, 5 (16%) for a medical cause unrelated to the drug (e.g. COVID infection, reduced performance status secondary to pre-existing Parkinson's), 3 (10%) for unacceptable toxicity (rash, Grade3 fatigue, muscle aches, memory issues), and 1 patient died (unrelated). Conclusions: In the RECORD study, predominantly the diagnosis of nmCRPC is based on conventional imaging. The majority of patients respond and tolerate Darolutamide well, comparable with the ARAMIS trial. There is a significant difference between time on Darolutamide for those with pre-treatment PSAdT of <6 months compared with ≥6 months. Further long-term toxicity, MFS and OS data will continue to be collected prospectively within the study.

Baseline characteristics associated with PSA progression-free survival in patients (pts) with high-risk biochemically relapsed prostate cancer: Results from the phase 3 PRESTO study (AFT-19).

208 Background: In the Phase 3 PRESTO study, intensified androgen deprivation therapy (ADT) with apalutamide (APA) with or without abiraterone acetate plus prednisone (AAP), administered for a finite treatment period of 52 weeks, prolonged prostate-specific antigen progression-free survival (PSA PFS) in pts with high-risk biochemically relapsed prostate cancer (BRPC). We evaluated baseline factors associated with PSA PFS in this study. Methods: PRESTO is a randomized phase 3, open-label trial in pts with BRPC following radical prostatectomy (RP) and PSA doubling time (PSADT) ≤ 9 months (mo), without distant metastases on conventional imaging (NCT03009981). Pts were randomized 1:1:1 to receive a finite 52-week treatment course with ADT, ADT + APA, or ADT + APA + AAP, stratified by PSADT (< 3 vs 3–9 mo), with post-treatment follow-up. Baseline factors associated with PSA PFS including Gleason sum at RP (6-7, 8, ≥ 9) were analyzed in a post hoc fashion. Results: 504 pts were randomized to ADT alone (N = 167), ADT + APA (N = 168) or ADT + APA + AAP (N = 169). Baseline patient characteristics including Gleason sum at diagnosis, serum PSA and PSADT at study entry, time interval from radical prostatectomy, and receipt of prior radiation (none, adjuvant, salvage) were well balanced across the three treatment arms. At the first planned interim analysis, both experimental arms significantly prolonged PSA PFS compared to the control arm (median 24.9 mo for ADT + APA vs 20.3 mo for ADT, HR = 0.52 (95% CI: 0.35–0.77); median 26.0 mo for ADT + APA + AAP vs 20.0 mo for ADT, HR = 0.48 (95% CI: 0.32–0.71)). Across the study cohort, Gleason sum ≥ 9 at diagnosis was associated with shorter PSA PFS (median 21.9 mo for Gleason ≥ 9 vs. 31.1 mo for Gleason 8 vs. 25.2 mo for Gleason 6-7, log-rank p-value = 0.0409). In addition, within each treatment arm, a shorter observed median PSA PFS was detected for patients with Gleason ≥ 9 prostate cancer. Serum PSA and PSADT at study entry, time from prior radical prostatectomy, and prior radiation were not associated with PSA PFS in the overall study cohort or in individual study arms. Conclusions: Gleason sum ≥ 9 prostate cancer at diagnosis was associated with shorter time to PSA progression following subsequent intensified ADT administered for a finite treatment interval in BRPC. Follow-up is ongoing to integrate genomic profiling of primary prostate cancer tissue with these results and validate with longer term endpoints including metastasis-free survival. Clinical trial information: NCT03009981 .

Characteristics of long-term responder (LTR) patients (pts) treated with androgen-receptor signaling inhibitors (ARSI) as a first-line treatment for metastatic castration-resistant prostate cancer (mCRPC): Real-world evidence from four high-volume institutions.

164 Background: ARSI [enzalutamide (ENZA) and abiraterone (ABI)] demonstrated to be efficacious as a first-line therapy for mCRPC, showing a median progression-free survival of 16 and 20 months (mos) in pivotal trials, respectively. Nevertheless, some pts of daily clinical practice show exceptionally prolonged disease control with very long duration of treatment. The present study aimed at identifying the characteristics of LTR pts who received one ARSI as a first-line for mCRPC. Methods: We retrospectively reviewed the clinical records of a consecutive series of 647 pts treated in the daily clinical practice with one ARSI as first-line mCRPC in four Italian high-volume Institutions. Pts who had previously received docetaxel in castration-sensitive setting were excluded. Pts received standard AA or ENZA doses (1,000 mg po daily plus prednisone 10 mg po daily or 160 mg po daily, respectively). ARSI were administered until progression and were followed according to each Institution policy. For each pt we recorded pre and post-ARSI clinical history, baseline characteristics, treatment details and clinical outcomes. Pts were considered as LTR in presence of an ARSI exposure ≥ 36 mos. LTR were compared to the progressed pts with an ARSI exposure < 36 mos. On-treatment pts with an ARSI exposure < 36 mos were not considered. Results: We identified 81 LTR pts (53 treated with ENZA and 28 treated with ABI). The median age was 76 yrs (range 56-89). The median treatment duration was 46.1 mos (range 36.4-88.6) and 52 pts were still on treatment. LTR were compared to no-LTR 415 pts (233 treated with ENZA and 182 treated with ABI). Compared to no-LTR, LTR pts showed longer PSA doubling time (PSADT) (PSADT) (p = 0.001) and time to mCRPC (p < 0.0001), lower levels of basal PSA (p = 0.01), and alkaline phosphatase (ALP) (p = 0.01), better ECOG PS (p = 0.01), lower Gleason score (p = 0.01), and less pain level (p = 0.04). ECOG PS, ALP, time to mCRPC and PSADT were all identified as independent predictors of time to treatment interruption in multivariate analysis. LTR showed an 89% decreased risk of death compared to no-LTR (HR = 0.11 IC95% 0.06-0.18). Conclusions: In our experience, several variables, which are usually considered as having a prognostic value, demonstrated to be able to predict the probability of prolonged disease control in mCRPC pts treated with first-line ARSI.

Phase 1 efficacy and pharmacodynamic results of exicorilant + enzalutamide in patients with metastatic castration-resistant prostate cancer.

145 Background: Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease with significant morbidity. Androgen receptor (AR) signaling is a key driver of tumor growth in mCRPC, and AR-targeted therapies are the mainstay for patients (pts) with locally advanced or metastatic disease. Enzalutamide (ENZA) is commonly used, but resistance typically develops within 1–2 years. The glucocorticoid receptor (GR) can substitute for the AR, providing a tumor escape pathway (Arora et al. Cell 2013). In the 22Rv1 CRPC xenograft model, the selective GR modulator exicorilant (EXI) combined with ENZA reduced tumor growth, supporting the hypothesis that dual antagonism of GR + AR may block this escape pathway. Safety and pharmacokinetics from the first study of EXI + ENZA in pts with mCRPC (NCT03437941) were previously presented (Linch et al. ESMO 2022). Here, we report efficacy and pharmacodynamic (PD) results from the same study. Methods: Segment 1 (Seg 1) of this phase 1 study evaluated open-label, fasting, BID dosing of EXI (140 or 180 mg) + ENZA 160 mg QD. Segment 2 (Seg 2) tested QD dosing of EXI with food in a double-blind design: All pts received EXI 240 mg + ENZA and were randomized 3:1 to EXI titration (to 280 mg followed by 320 mg) or to remain on EXI 240 mg + placebo. Efficacy assessments included radiographic response and changes in prostate-specific antigen (PSA) levels. PSA was collected prior to study entry and PSA doubling times were calculated before and during treatment. PD analyses included baseline (BL) tumor GR expression and modulation of GR target genes in whole blood. As not all pts enrolled in Seg 1 were ENZA naïve, efficacy data are reported for Seg 2 only. Data cutoff date: July 7, 2022. Results: 39 pts were enrolled (Seg 1: 14, irrespective of prior ENZA exposure; Seg 2: 25, on a stable ENZA dose with rising PSA, defined as a 25% increase over nadir and absolute value >1 ng/mL). In Seg 2, there were no radiographic responses, 18 pts had a best overall response of stable disease per PCWG3, and 1 pt achieved a PSA response (≥50% PSA reduction from BL). BL tumor GR expression was detectable in all assessed tumors. PD analyses demonstrated EXI modulation of GR target genes, such as CDKN1C. Comparable PD effects were observed across EXI doses (240–320 mg QD). While BL 24-h urinary free cortisol (UFC) for most pts was within the normal range, improvements in PSA doubling times after treatment with EXI + ENZA were predominantly observed in pts with higher BL UFC ( P<0.05). Conclusions: This study did not include an ENZA-alone arm and was thus not designed to assess the contribution of EXI to the efficacy of the EXI + ENZA combination. In heavily pretreated pts with prior ENZA exposure, 1 PSA response and no radiographic responses were observed. PD analysis confirmed systemic GR modulation. Instances of PSA doubling time improvements were observed in pts with relatively higher UFC. Clinical trial information: NCT03437941 .

Metastasis-directed ablative radiotherapy in castrate-resistant oligometastatic prostate cancer: A retrospective study of 8 high-volume French centers from the COLib (Cercle des Oncologues Libéraux).

152 Background: In castrate-resistant oligo metastatic prostate Cancer (CRoligoMPC), the benefit of metastases-directed ablative radiotherapy (MDRT) is poorly investigated. Our study retrospectively reviewed the cases of CR oligoMPC treated with MDRT. Methods: Patients receiving MDRT in CRoligoMPC were retrospectively reviewed. Patients were included if: they had < 5 metastases on metabolic work-up, testosterone is < 50 ng/mL, metastases received MDRT. Patients and disease's data were collected: age, Gleason score, time to metastases, time to castration resistance; medical treatments, metastases location (bone versus node); radiotherapy regimens, PSA (PSA doubling time PSADT at the time of MDRT and PSA response). Progression was assessed according to PCWG criteria. PFS and OS are defined as the time from MDRT to first progression, for PFS and death date for OS. Kaplan-Meier analysis was used to summarize time-to-event variables and curves were compared with the log-rank test. A logistic regression was used to identify predictive factors of PFS. Results: the median follow up is 25.6 months.107 patients met inclusion criteria, among those 197 metastases received MDRT. Median age at MDRT time was 73 years. Median hormonosensitivity duration was 38 months (4-225). Forty six patients had metastases at the time of hormonosensitivity and 61 developed metastases in the castration resistance (CR)period (spartan-like population). PSA doubling time at the time of MDT RT was < 12 months in 88%. A median number of 2 metastases per patient was treated (1-4), 54% had RT on bony metastases only, 38% on nodes, 8% on bone + node. In 61 patients with metastases at the time of CRPC, 34.5% received a CR systemic medication before or concomitantly to MDRT, 39% received CR medication at progression, 23.5% never received CR treatment (unknown in 3%). OS is 93% at 2 years and 81.4% at 3 years. For node-only metastases, 2y OS is 100% versus 89% for bone metastases. Median PFS is 12.6 months (IC 95% [9.6; 17]). Metastases location, grade group, PSA or hormonosensitivity duration were not related to PFS in a univariate survival analysis. PFS was 10.2 months when PSA Doubling time was < 6 months, versus 18.2 months when it exceeded 6 months (NS). The PSA 50% response was studied in the Spartan like population, it was 83.4% in patients receiving MDRT AND new generation hormonotherapy; 31% in those who received MDRT without new generation hormonotherapy, and 20% in those who received MDRT at the time of progression of oligometastases occurring under new generation hormonotherapy. Conclusions: In a population of CR oligoM PC with short PSA DT, MDRT leads to a PFS of 12.6 months and to a 3y OS of 81.4%. In this setting, androgen receptor targeting agents are the standard of care. Whether adding MDRT could improve prognosis should be prospectively evaluated.

Effect of equal access to care on prostate cancer progression in minority patients.

33 Background: Prostate cancer (PC) is an androgen-dependent disease that initially responds to androgen deprivation therapy (ADT); however, it can become resistant to therapies that reduce testosterone levels, signaling a transition to non-metastatic, castration-resistant PC (nmCRPC). Racial disparities are known in PC, with black and Hispanic men presenting with more advanced disease and having a higher mortality rate compared to non-Hispanic white men. The goal of treatment management in patients with nmCRPC is to prevent or delay metastases. This study examines the disease progression observed among patients with nmCRPC who received care and treatment in an equal access healthcare system, the Veterans Health Administration. Methods: Patient information was obtained from the Veterans Affairs (VA) Clinical Cancer Registry (VACCR) and the VA Corporate Data Warehouse (CDW) to identify patients who were diagnosed with prostate cancer at the VA and later developed nmCRPC, defined as (1) evidence of a rising prostate-specific antigen (PSA), i.e., 2 consecutive increases in PSA concentration over a baseline value; (2) evidence of ongoing androgen deprivation consisting of a serum testosterone level of ≤50 ng/dL (≤2.0 nmol/L); and (3) the absence of metastatic disease as evidenced in radiology reports. Treatments of nmCRPC were identified by review of NCCN Prostate Cancer Guidelines and extracted from CDW pharmacy dispensation records and indexed at nmCRPC diagnosis. A multivariate Cox proportional hazard model was used to identify time to metastatic disease in nmCRPC patients. Results: 654,148 patients were diagnosed with PC and received care in the VA from 2006 to 2021; of these, 12,992 developed nmCRPC, of whom 7,323 (56%) were white, 3,671 (28%) were black, 826 (6%) were Hispanic, and 1,172 (9%) were reported as other. Compared with white men at nmCRPC diagnosis, black men were younger (70 years vs. 74 years) while Hispanic men were older (75 years). White and Hispanic men had similar PSA at nmCRPC (10.2 ng/mL and 10.4 ng/mL), while the PSA for black men was higher (14.3 ng/mL). Similar treatment patterns were observed in all patients regardless of race; with ADT (60%), bicalutamide (24%), and finasteride (3%), the most frequently used first-line treatments. The mean time from nmCRPC to metastatic CRPC was 27.5 days for white men, 31.6 days for black men, 27.6 for Hispanic men, and 26.0 days for others. After adjusting for age, comorbidities, PSA doubling time, and treatment, the hazard ratio (HR) for developing metastatic disease was 0.85 (95% CI: 0.80–0.90, <0.001) for black men, 0.70 (95% CI: 0.62–0.78, <0.001) for Hispanic men, and 1.07 (95% CI: 0.99–1.16, <0.001) for others. Conclusions: These results suggest that when provided with care and treatment in an equal access healthcare system, black and Hispanic patients with nmCRPC are less likely to progress to metastatic CRPC than non-Hispanic white men.

Efficacy of subsequent treatments in patients who progressed to mCRPC following treatment with apalutamide for nonmetastatic castration-resistant prostate cancer (nmCRPC): A post-hoc analysis of the SPARTAN phase III trial.

157 Background: Apalutamide (Apa) delays the onset of metastases and extends survival in nmCRPC. However, the benefit of subsequent therapy for metastatic castration resistant prostate cancer (mCRPC) following progression on Apa remains inadequately explored. Methods: A post-hoc analysis of SPARTAN, a randomized phase III (NCT01946204), double-blind, placebo-controlled trial with Apa for the treatment of men with nmCRPC was undertaken in order to assess the impact of post-protocol treatment. Patients included in this analysis were SPARTAN patients who developed mCRPC while on Apa and received a first subsequent therapy for mCRPC (the “Next Cohort”). The index date of the analysis was the initiation of first subsequent treatment for mCRPC. The baseline characteristics of the Next Cohort (reported from the time of initial randomization because updated characteristics at the index date could not be derived) were compared to those of the ITT Apa arm in SPARTAN. Subsequent overall survival (sOS) and subsequent progression-free survival per physician assessment (sPFS) were calculated from the index date using Kaplan-Meier method. Results: At study completion, 237 patients remained on Apa without progression, while 311 were included in the Next Cohort. Of these, 241 (77.5%) received abiraterone acetate plus prednisone (AAP) provided by the sponsor as an option as first subsequent treatment, 29 (9.3%) received docetaxel; 20 (6.4%) enzalutamide and 21 other treatments (6.8%). Compared to the ITT Apa arm in SPARTAN, a higher proportion of the Next Cohort had PSA doubling time ≤6 months (79.1% vs 71.5%) and a PSA value above median at baseline, and experienced poorer PSA response (51% PSA90 overall response rate vs 62%) whilst on apalutamide treatment. The median sPFS and sOS were 6.8 months (95% confidence interval, CI, 5.8-7.9) and 20.0 months (95% CI, 17.0-22.6), respectively. Choice of subsequent next treatment did not appear to have an impact on sPFS and sOS. Conclusions: Limitations of this analysis include its retrospective nature and the lack of randomization to first line mCRPC therapy and related potential confounding, and the inclusion of patients who had progressed at SPARTAN study completion with associated poorer prognosis. Nevertheless, the analysis suggests comparable efficacy of selected first line mCRPC therapies, following progression on Apa for nmCRPC. Clinical trial information: NCT01946204 . [Table: see text]

PRIMARY2: A phase III, multi-centre, randomised controlled trial investigating the additive diagnostic value of [68Ga]Ga-PSMA-11 PET/CT in men with negative/equivocal MRI in the diagnosis of clinically significant prostate cancer.

TPS397 Background: Multi-parametric magnetic resonance imaging (MRI) has an established role for the diagnosis of clinically significant prostate cancer (sPCa), with superior diagnostic accuracy compared with transrectal ultrasound guided prostate biopsy alone. PRIMARY demonstrated significant improvement in sensitivity (97% vs 83%) and negative predictive value (91% vs 72%) with the addition of [68Ga]Ga-PSMA-11 PET/CT (PSMA PET/CT) vs MRI alone. Furthermore, 38% of patients with PI-RADS 2 or 3 were true negative on PSMA PET/CT, a population which may potentially benefit from avoiding transperineal prostate biopsy (TPPB). We hypothesize that the addition of PSMA PET/CT is non-inferior to MRI for the detection of sPCa in men with PI-RADS 2-3 disease, while providing the advantages of reducing unnecessary biopsies and limiting to targeted-only TPPB. Methods: This multi-centre, two-arm, randomized controlled, phase III trial will recruit 660 men with high clinical suspicion of sPC. Participants will be randomized in a 1:1 ratio in permuted blocks, stratified by center. In the experimental arm, participants will undergo a pelvic PSMA PET/CT. Local and central reviewers will interpret independently, based on the PRIMARY Score. Participants with a positive result will undergo targeted-TPPB, whereas those with negative PSMA PET/CT will avoid biopsy. In the control arm, all participants undergo template-TPPB. Patients will continue follow-up for subsequent clinical care for up to two years post-randomization. Key eligibility criteria include an MRI result of PI-RADS 2 with at least one red flag [PSA density >0.1, abnormal digital rectal examination (DRE), strong family history, BRCA mutation, PSA >10, PSA doubling time <36 months, PSA velocity >0.75/year], or PI-RADS 3, having never undergone a prostate biopsy, <cT3 on DRE, and PSA ≤20 ng/mL. The co-primary objectives are to estimate the percentage difference in sPCa between the experimental and control arms, and the percentage of participants who avoid TPPB in the experimental arm. The primary endpoints will be analyzed on the intention-to-treat principle. The main secondary objectives are the percentage difference between arms in insignificant prostate cancer, in complications following biopsy, in health-related quality of life, generalized anxiety, cancer worry, as well as the health economics impact. Patient enrolment began in March 2022, with recruitment expected to take 36 months. Clinical trial information: NCT05154162 .

FORMULA-509: A multicenter randomized trial of post-operative salvage radiotherapy (SRT) and 6 months of GnRH agonist with or without abiraterone acetate/prednisone (AAP) and apalutamide (Apa) post-radical prostatectomy (RP).

303 Background: Six months of a GnRH agonist with SRT is a standard of care for patients with unfavorable features and a detectable PSA post-RP. FORMULA-509 was designed to evaluate whether adding six months of AAP and Apa to this regimen could improve outcomes. Methods: FORMULA-509 (NCT03141671) is an investigator-initiated, multi-center, open-label, randomized trial. Patients had PSA≥0.1 post-RP and one or more unfavorable features (Gleason 8-10, PSA>0.5, pT3/T4, pN1 or radiographic N1, PSA doubling time <10 months, negative margins, persistent PSA, gross local/regional disease, or Decipher High Risk). All patients received SRT plus 6 months of GnRH agonist and randomization was to concurrent bicalutamide 50 mg or AAP 1000mg/5mg + Apa 240mg QD. Radiation to pelvic nodes was required for pN1 and optional for pN0. The primary endpoint was PSA progression-free survival (PFS) and secondary endpoint was metastasis-free survival (MFS) determined by conventional imaging. The study was powered to detect a HR of 0.50 for PFS and a HR of 0.30 for MFS, each with 80% power and one-sided type I error of 0.05. Stratification was by PSA at study entry (>0.5 vs.≤0.5) and pN0 vs pN1. Analyses within these subgroups were pre-planned. Results: 345 participants (332 evaluable) from 9 sites were randomized from 11/24/2017 to 3/25/2020 (172 bicalutamide, 173 AAP/Apa). Median follow-up was 34 (6-53) months; 29% were pN1 and 31% had PSA >0.5 ng/mL. The HR for PFS was 0.71 (90% CI 0.49-1.03), stratified one-sided log-rank p=0.06 (3-year PFS was 68.5% bicalutamide vs 74.9% AAP/Apa). The HR for MFS was 0.57 (90% CI 0.33-1.01), stratified one-sided log rank p=0.05 (3-year MFS was 87.2% bicalutamide vs 90.6% AAP/Apa). In a pre-planned analysis by stratification factors, AAP/Apa was significantly superior for patients with PSA >0.5 for PFS [HR 0.50, (90% CI 0.30-0.86), p=0.03 (2-sided); 3-year PFS 46.8% bicalutamide vs. 67.2% AAP/Apa] and for MFS [HR 0.32 (90% CI 0.15-0.72), p=0.01 (2-sided); 3-year MFS 66.1% bicalutamide vs. 84.3% AAP/Apa.] No statistically significant benefit was detected in pre-planned analyses of stratification subgroups defined by PSA≤0.5, pN0, or pN1. Adverse events were consistent with the known safety profiles of the agents being studied, with more rash and hypertension in the AAP/Apa arm. Conclusions: Although this primary analysis did not meet the pre-specified threshold for statistical significance, it does strongly suggest that the addition of AAP/Apa to SRT+6 months of ADT may improve PFS and MFS, particularly in the subgroup of patients with PSA>0.5 where a pre-planned subgroup analysis by stratification factors observed a statistically significant benefit for both PFS and MFS. Clinical trial information: NCT03141671 .

P-MCP treatment in non-metastatic biochemically relapsed prostate cancer (BRPC-M0): Final long-term results of a prospective phase II study.

162 Background: 30% of patients with localized PC will have a biochemical relapse post local therapy. Their optimal treatment remains elusive. While androgen deprivation therapy is effective in reducing PSA level, its long-term benefit remains undefined, and it is toxic. Thus, evaluation of new nontoxic compounds in these patients is warranted. PectaSol-C modified citrus pectin (P-MCP) is an inhibitor of galectin-3 protein, which is involved in prostate cancer pathogenesis. We herein report the final long-term results of a multi-center phase 2 study of P-MCP treatment in BRPC-M0. Methods: Patients with BRPC-M0 were enrolled and treated with P-MCP, 4.8 grams X 3/day, for 6 months (first phase of trial). Patients without PSA progression and/or with improvement of PSA doubling time (PSADT), and with negative scans, were treated for an additional 12 months (second phase of trial). Results: 59 patients were initially enrolled. After initial 6 months of therapy, 46 patients (78%) without disease progression entered the second phase of additional 12 months therapy. Among them, 7 patients withdrew consent and chose to continue therapy out of pocket. Of the remaining 39 patients, after another year of therapy (total of 18 months), 85% (n=33) had an overall long-term response, with a decreased/stable PSA (62 %, n=24), and improvement of PSADT (90 %, n=35), and with negative scans. No patient had grade 3/4 toxicity. Conclusions: P-MCP may have a durable long-term efficacy in patients with BRPC-M0. Clinical trial information: NCT01681823 .

Real-world prostate-specific antigen (PSA) response and disease progression among patients with non-metastatic castration-resistant prostate cancer (nmCRPC) initiated on apalutamide (APA).

69 Background: For patients with nmCRPC, APA with androgen deprivation therapy is an important therapeutic option with demonstrated efficacy in improving metastasis-free survival (MFS), and other clinical outcomes. However, there is limited real-world information on these outcomes among patients with nmCRPC treated with APA. This study describes PSA response and MFS among patients with nmCRPC treated with APA in the United States as compared to the SPARTAN registrational trial. Methods: Clinical data from 2/2017 to 4/2022 collected from 77 community-based urology practices were used to evaluate patients with nmCRPC who received ≥1 APA dispensation (index date being the date of first dispensation). Patients were excluded if they had previously used another next-generation antiandrogen or had <12 months of pre-index clinical activity. PSA response was evaluated while on treatment and was defined as a post-index ≥90% decline (PSA90) in PSA from baseline (using the closest PSA value within 13 weeks prior to or on the index date) and was reported in patients with ≥1 post-index PSA test result by 3 months, 6 months, 12 months and overall. Disease progression was evaluated as MFS and defined as the time from index date to the occurrence of metastasis or death, whichever occurred first. Disease progression was described using Kaplan-Meier (KM) analysis by 6-month increments up to 24 months post-index. Results: A total of 406 patients with nmCRPC (mean age 78.8 years, 73% white, mean baseline PSA 9.0 ng/mL) were identified. Among 96 patients with available data, the mean (median) baseline PSA doubling time was 9.9 (7.5) months. The mean (median) treatment duration was 434 (305) days. PSA90 rates were 40% by 3 months, 51% by 6 months, 56% by 12 months, and 58% overall. KM rates for MFS were 95% at 6 months, 90% at 12 months, 82% at 18 months, and 75% at 24 months. PSA response and MFS for real-world patients were consistent with those observed from the SPARTAN trial. Conclusions: This real-world study of patients with nmCRPC demonstrates that APA treatment resulted in early, deep PSA responses, consistent with the SPARTAN trial. Moreover, MFS observed in the real-world was similar to that of the SPARTAN trial. [Table: see text]

Real-world use of darolutamide, enzalutamide, and apalutamide for non-metastatic castration-resistant prostate cancer (DEAR).

332 Background: Second-generation androgen receptor inhibitors (ARIs) are the preferred treatment for patients (pts) with non-metastatic castration-resistant prostate cancer (nmCRPC). In this setting, an important therapeutic goal is to minimize adverse events (AEs) and prolong time on ARI treatment. This is the first study to assess real-world (RW) utilization and outcomes of all currently available ARIs, darolutamide (daro), enzalutamide (enza), and apalutamide (apa) in pts with nmCRPC. Methods: DEAR (NCT05362149) is a retrospective observational chart review using electronic medical records from the Precision Point Specialty network of US urology practices. Eligibility criteria included nmCRPC diagnosis, no previous treatment with a novel hormonal agent, and ARI treatment initiation for the first time from August 2019 to March 2022. Pts were classified into 3 cohorts based on the first prescribed ARI in the nmCRPC stage. We present an interim report including the primary composite endpoint (DIS/MET): proportion of pts who discontinued initial ARI treatment (DIS) or progressed to metastasis (MET); and secondary endpoints: time to DIS/MET and underlying reasons. Results: In total, 666 pts were included (daro/enza/apa, n=276/280/110). The proportion of pts starting treatment with daro increased during the study period relative to enza or apa, which declined or remained stable, respectively. Median age (80/79/80 years), White race (68%/69%/74%) and median PSA doubling time (6.7/6.0/7.8 months) at baseline were similar in the daro/enza/apa cohorts, respectively. Median length of follow-up was similar. Fewer pts had a DIS/MET event during the study in the daro cohort (35.9%), compared with enza or apa (52.1%/50.9%); this trend was seen within 6 to 18 months after ARI start. Median time to DIS/MET was 33.4/20.8/18.5 months for daro/enza/apa, respectively. Most common reasons for DIS/MET in the daro/enza/apa cohorts were AEs (8.3%/15.0%/12.7%), death (3.3%/5.4%/2.7%), and MET (14.9%/22.9%/18.2%). Conclusions: This RW study in the US shows that, despite similar baseline characteristics, fewer nmCRPC pts treated with daro had DIS/MET (especially due to AEs/MET) versus enza and apa, and the time to this event was longer in the daro cohort. These findings may be attributed to daro being a structurally distinct ARI with low potential for blood–brain barrier penetration. [Table: see text]

A phase II study of rucaparib monotherapy in nonmetastatic, hormone-sensitive prostate cancer (nmHSPC) with “BCRAness” genotype (ROAR).

364 Background: Prostate cancer (PCa) patients (pts) with DNA repair defects (aka “BRCAness”) generally have more aggressive disease and a worse overall prognosis compared to men without BRCAness (PMID: 33781305). Biochemical recurrence (BCR) develops in almost one-third of men with PCa after treatment with local therapy. We hypothesized that treatment with rucaparib monotherapy in men with systemic treatment naïve high-risk nmHSPC would result in acceptable disease control, allow a delay of androgen deprivation therapy (ADT) and the onset of metastasis. Methods: This is a single-arm, open-label, phase II trial; eligibility criteria: (1) Histologically proven prostate adenocarcinoma, presence of one of the following alterations in (by soft tissue or liquid biopsy): BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, NBN, PALB2, RAD51C, RAD51D, RAD51, RAD51B, (2) No radiographic evidence of metastatic disease by conventional scans (3) PSA doubling time of ≤10 months. The primary endpoint: PSA progression-free survival (PSA-PFS). Secondary endpoints: safety, the proportion of pts with a PSA 50% response (PSA50), and an undetectable PSA. Results: Seven pts were enrolled in the study with the following pathogenic alterations: ATM (n=3), BRCA2 (n=2), BRCA1 (n=1), BRIP1 (n=1), RAD51(n=1), and received treatment with rucaparib at 600 mg twice daily. A 4-week treatment duration comprised one cycle. The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI: 0 - 85.11 months). 2/7 patients achieved PSA50; both had nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 pt each). No dose-limiting toxicities or severe AEs were seen. The study was prematurely terminated in June 2022 after the accrual of 7 pts because next-generation scans (e.g., PSMA-PET) became the standard of care for pts with BCR. Conclusions: Rucaparib demonstrated acceptable toxicity and preliminary efficacy in pts with PCa with BCR. Gene alteration-specific efficacy will be presented in the meeting. Limitations: Small cohort, no comparison arm. Hence results should be interpreted cautiously but generally consistent with larger prospective trials of PARP inhibitors. Clinical trial information: NCT03533946 . [Table: see text]

Randomized, double-blinded phase II study of ketoconazole (keto), hydrocortisone (HC), and anti-PSMA antibody J591 labeled with 177Lu or 111In in patients (pts) with high-risk non-metastatic (met) castration-resistant prostate cancer (M0 CRPC).

LBA21 Background: Up to 1/3 of pts develop biochemical relapse following primary therapy. Many are not cured with salvage local therapy, likely because of undetectable distant disease. PSMA is expressed on most PC and can be targeted by radiolabeled J591. 177Lu is a predominantly β-emitting radionuclide and also has γ emission which allows imaging. 111In is predominantly a γ emitter, also with some auger emission for therapy. Hormonal therapy is effective and may increase PSMA expression and radiosensitize. In this DOD-funded study initiated in the pre-PSMA PET and AR signaling inhibitor era, we hypothesized that 177Lu prolongs 18-month (mo) met-free survival (MFS) more than 111In in pts with high risk, M0 CRPC when targeting PSMA via J591 in combo with keto and HC. Methods: Pts with high-risk M0 CRPC defined by PSA DT < 8 mo and/or absolute PSA > 20 ng/mL and serum testosterone < 50 ng/mL with no evidence of metastatic disease on CT/MRI and bone scan were eligible. Treatment included a minimum 4 week lead-in with keto 400 mg TID and HC 20 mg AM, 10 mg PM (both of which could be continued until unacceptable toxicity or development of mets) and a single infusion of J591 with 2:1 randomization to 177Lu (70 mCi/m2) or 111In (5 mCi) in double-blinded fashion. The final version of the protocol was designed to randomize 55 pts for 80% power to detect a difference in 18-mo MFS with one-sided alpha of 10%. Secondary endpoints include median MFS, PSA response, overall survival, and toxicity. Results: 55 pts with median age 68 (range 52 - 88), 75% prostatectomy, 23% primary radiation, 2% primary ADT; 19% local salvage therapy. Median PSA doubling time 3 mo (range 0.87 – 7.85), median baseline PSA 8.0 (range 1-78). In intent to treat analysis (5 without imaging and 4 lost to follow up by 18 mo), 50% developed mets by 18 mo with 177Lu vs 76% with 111In (p=0.066). Median MFS was 23.8 mo vs 20.8 mo, and biochemical PFS was 18.67 vs 8.87 mo, favoring 177Lu in analyses censoring start of new treatment. Confirmed >50% PSA decline occurred in 82% with 177Lu and 71% with 111In. Grade >3 heme AEs were more common with 177Lu vs 111In, including neutropenia (57% vs 11%, with 1 febrile neutropenia) and thrombocytopenia (77% vs 11%, with 25% vs 6% platelet transfusions), whereas Gr >3 non-heme AEs were less common with 177Lu vs 111In, including abdominal pain (0 vs 11%), ALT increase (3.3% vs 22%), and diarrhea (0 vs 22%). Conclusions: Anti-PSMA mAb J591 with keto/HC when radiolabeled with 177Lu leads to improved 18-month met-free survival vs 111In. Most pts had significant PSA decline with either version of radiolabeled J591 with keto/HC. Hematologic toxicity is more common with 177Lu. This supports the development of anti-PSMA radioimmunotherapy for low volume advanced PC, though the optimal radionuclide and targeting agent is unknown. Clinical trial information: NCT00859781 .

Comparison of prognostic characteristics between vintage and novel androgen receptor-axis-targeted drug among Japanese patients with non-metastatic castration-resistant prostate cancer: A multi-institutional study of Japanese Urological Oncology Group (JUOG).

163 Background: We conducted a multicenter study, 1) to verify the prognostic difference between novel androgen receptor-axis–targeted (ARAT) drug and vintage drug (Vintage) and, 2) to identify the prognostic PSA doubling time (PSADT) among Japanese non-metastatic castration-resistant prostate cancer (nmCRPC) patients. Methods: Of 515 patients diagnosed and treated for nmCRPC at 25 JUOG participating centers, including Chiba University Hospital, 489 patients with complete clinical characteristics were included. The association between each clinical factor, including drug types, PSADT, progression-free survival (PFS), and overall survival (OS) were analyzed, retrospectively. Results: The median age at nmCRPC diagnosis was 72 years, PSA was 3.24 ng/ml, and the observation period was 980 days. nmCRPC PFS and OS were 22 and 95 months, respectively. nmCRPC first-line therapy included Vintage + LH-RH alone: 197 cases/ARAT: 285 cases /Docetaxel (DOC): 7 cases. In the search for optimal PSADT (3-12M), PFS and OS correlated best at 10M (HR 1.64, p=0.005) and 4M (HR 2.63, p<.0001), respectively. ARAT(DOC) significantly prolonged PFS (HR 3.15, p<.0001) compared to Vintage, however, did not affect OS (HR 1.09, p=0.697) nor combined PFS (HR 0.94, p=0.733). The result was consistent, even after adjustment of the patient`s background by the propensity score matched analysis (n=145 in each arm), such as PFS (HR 0.35, p<.0001), OS (HR 1.16, p=0.598) and Combined PFS (HR 0.66, p=0.133). Multivariate analysis showed that PSADT was an independent prognostic factor for PFS (PSADT 10M: HR 3.1 p<.0001) and OS (PSADT 4M: HR 2.8, p=0.002). Conclusions: ARAT(DOC) prolonged PFS, but not OS, compared to Vintage in Japanese nmCRPC patients. PSADT (4-10M) may represent a useful tool in predicting prognosis and constructing treatment strategies for Japanese nmCRPC patients. [Table: see text]

Low hemoglobin and PSA kinetics are prognostic factors of overall survival in metastatic castration-resistant prostate cancer patients

The objective of this study was to identify the prognostic factors and to propose a new risk model in metastatic castration-resistant prostate cancer (mCRPC) patients. The clinical data were retrospectively obtained for 102 mCRPC patients who received cancer treatment between 2005 and 2018 at the University of Tokyo Hospital. We investigated clinical and pathological parameters, including prostate-specific antigen (PSA) kinetic profiles under androgen deprivation treatment, and identified predictors of overall survival (OS). The median age and PSA were 73 (Interquartile range [IQR], 68–79) years and 5.00 (IQR, 2.77–13.6) ng/ml. The median follow-up was 34 (IQR, 17–56) months. In univariate analysis, ‘lymph node metastasis’, ‘Hemoglobin (Hb)’, ‘Time to nadir PSA (TNPSA)’, ‘PSA doubling time (PSADT)’, ‘Time to CRPC’, and ‘presence of pain’ were prognostic factors. Multivariate analysis identified ‘Hb < 11 g/dL’, ‘TNPSA < 7 months’ and ‘PSADT < 5 months’ as independent prognostic factors of OS. The high-risk group (patients with two or three factors) demonstrated shorter OS (23 vs. 50 months) with an increased risk of death (HR = 2.997; 95% CI 1.632–5.506; P = 0.0004). The proposed risk stratification model may contribute to the prediction of survival and provide supportive information in treatment decision-making.

The natural history of a delayed detectable PSA after radical prostatectomy

IntroductionMen with a detectable PSA after radical prostatectomy (RP) are often offered salvage therapy while those with an undetectable PSA are monitored. We aim to better characterize the natural history of men with an initially undetectable PSA who subsequently developed a detectable PSA > 6 months after RP.MethodsRetrospective analysis of men who underwent RP for clinically localized prostate cancer at the University of California, San Francisco from 2000 to 2022. The primary outcome was biochemical recurrence, defined as 2 consecutive PSA > = 0.03 ng/mL starting 6 months after surgery. Secondary outcomes were salvage treatment, post-salvage treatment, metastasis free survival (MFS), prostate cancer specific mortality (PCSM), and all-cause mortality (ACM). This cohort was compared to a previously described cohort who had an immediately detectable post-operative PSA.ResultsFrom our cohort of 3348 patients, we identified 2868 men who had an undetectable post-op PSA. Subsequently, 642 men had a delayed detectable PSA at a median of 25 months (IQR 15, 43) with median follow-up of 72 months after RP. PSA at time of failure was <0.10 ng/mL for 65.7% of men. Of those with a delayed detectable PSA, 46% underwent salvage treatment within 10 years after RP at a median PSA of 0.08 ng/mL (IQR 0.05, 0.14). High CAPRA-S score (HR 1.09, CI 1.02–1.17, p = 0.02) and PSA doubling time (PSA-DT) of <6 months (HR 7.58, CI 5.42–10.6, p < 0.01) were associated with receiving salvage treatment. After salvage treatment, 62% of men had recurrent PSA failure within 10 years. Overall, MFS was 92%, PCSM 3%, and ACM 6% at 10 years. For those who received tertiary treatment for recurrent PSA failure, MFS was 54%, PCSM 23% and ACM 23% at 10 years’ time.ConclusionsMen who develop a detectable PSA > 6 months post-operatively may have excellent long-term outcomes, even in the absence of salvage therapy.

The Safety and Efficacy of Salvage Stereotactic Radiation Therapy in Patients with Intraprostatic Tumor Recurrence After Previous External Radiation Therapy: Phase 1 Results from the GETUG-AFU 31 Study

BackgroundThere is no consensus on the best local salvage treatment for prostate cancer recurrence after primary external beam radiotherapy. Prospective data on stereotactic body radiation therapy (SBRT) are very scarce. ObjectiveTo determine the optimal dose regimen for salvage SBRT. Design, setting, and participantsThe present report concerns the phase 1 part of the GETUG-AFU 31 multicenter open-label study. The main inclusion criteria were histologically proven biochemical recurrence, clinical stage T1-T2 upon relapse, multiparametric magnetic resonance imaging data, prostate-specific antigen (PSA) level ≤10 ng/ml prior to salvage SBRT, PSA doubling time >10 mo, and an International Prostate Symptom Score of ≤12. InterventionFive or six fractions of 6 Gy were delivered using focal SBRT. Outcome measurements and statistical analysisDose-limiting toxicity (DLT) was defined as grade ≥3 gastrointestinal or genitourinary tract toxicity, or any grade 4 toxicity (according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03) occurring in the first 18 wk following treatment initiation. A time-to-event continual reassessment method was used to select the dose regimen. Results and limitationsTwenty-one patients were treated (median [interquartile range] age: 76.8 yr [72.2–80.8]), including 12 at 6 × 6 dose level. No DLT was observed. The acute grade 2 genitourinary tract toxicity rate was 19%. With a median follow-up of 12.3 mo, the estimated cumulative incidence of late grade 2 genitourinary toxicity was 41.2% (95% confidence interval: 18.1–63.1%). No grade >2 genitourinary toxicity and no grade ≥2 gastrointestinal toxicity were reported. All treated patients were alive and relapse free at the last follow-up. ConclusionsA 6 × 6 Gy dose regimen was selected for our phase 2 study of salvage SBRT. With a short follow-up period, the level of toxicity appears to be acceptable. Patient summaryThere is no consensus on the best local treatment for patients with local relapse after radiotherapy for prostate cancer. Prospective data are very scarce. Our early phase trial allowed us to recommend six fractions of 6 Gy using high-precision radiotherapy for further studies.

Recurrence characteristics after focal salvage HDR brachytherapy in prostate cancer

Background and purposeRadiorecurrent prostate cancer is often confined to the prostate, predominantly near the index lesion. The purpose of this study was to look at recurrence characteristics in patients treated with focal salvage high dose-rate (HDR) brachytherapy. Materials and methodsPatients treated with MRI-guided HDR brachytherapy, with a single fraction of 19 Gy from July 2013 to October 2021 as focal salvage treatment, were prospectively included in the current study. Imaging data were collected regarding the occurrence of local, regional and distant recurrences, including location of local recurrences (LR) in relation to the HDR radiotherapy field. ResultsOne hundred seventy-five patients were included after focal salvage HDR brachytherapy (median follow-up 36 months (IQR 23–50)). Three-years biochemical recurrence-free survival, LR-free survival, in-field LR-free survival, out-of-field LR-free survival, any-recurrence-free survival and ADT-free survival were 43% (95%CI 34%–52%), 51% (41%–61%), 70% (61%–80%), 92% (88%–97%), 42% (32%–52%) and 86% (80%–92%), respectively. Larger GTV-size and shorter PSA doubling time were associated with in-field LR in multivariable analysis. ConclusionAfter focal salvage HDR brachytherapy with a dose of 1x19 Gy for local prostate cancer recurrence, subsequent recurrences are mostly local and in-field.

Clinical significance of completion of radium-223 treatment and acute adverse events in patients with metastatic castration-resistant prostate cancer.

In the treatment of castration-resistant prostate cancer (CRPC) with bone metastases, radium-223 dichloride (Ra-223) is the only bone-targeted drug that shows survival benefits. Completing six courses of Ra-223 treatment is thought to be associated with better patient survival, but this treatment has a relatively high rate of acute adverse events. This retrospective study included 85 patients from 12 institutions in Japan to investigate the clinical significance of the completion of Ra-223 treatment and acute adverse events in CRPC patients. Six courses of Ra-223 treatment were completed in 65.9% of the patients. Grade 3 or higher acute adverse events were observed in 27.1% of patients. The prostate specific antigen and alkaline phosphatase declined at 26.9% and 87.9%, respectively. The overall survival rates at 12 and 24 months were 80.7% and 63.2%, respectively. Both completion of six courses of Ra-223 treatment and absence of grade 3 or higher acute adverse events were associated with longer overall survival. In univariate analysis, factors related to the history of treatment (five or more hormone therapy agents and cytotoxic chemotherapy) and hematological parameters (Prostate specific antigen (PSA) doubling time, alkaline phosphatase, hemoglobin, albumin, and serum calcium) were associated with completing six courses of Ra-223 treatment without experiencing grade 3 or higher acute adverse events. Multivariate analysis showed that a history of chemotherapy, PSA doubling time, hemoglobin, and serum calcium showed statistical significance. We built a predictive score by these four factors. Patients with lower scores showed higher rates of treatment success (p<0.001) and longer overall survival (p<0.001) with statistical significance. Accomplishing six courses of Ra-223 treatment without grade 3 or higher acute adverse events was a prognostic factor in patients with mCRPC treated with Ra-223. We built a predictive score of treatment success and need future external validation.