PSA Doubling Time Research Articles

Effectiveness and safety of enzalutamide and apalutamide in the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC): a multicenter retrospective study.

Phase III clinical trials demonstrated the efficacy of enzalutamide and apalutamide in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and PSA doubling time ≤10months. Although these drugs have been shown to vary in their adverse event (AE) profiles, the differences in their efficacy profiles remain to be evaluated. Therefore, this retrospective study was conducted to evaluate the efficacy of these drugs in patients with nmCRPC. This study evaluated 191 patients with nmCRPC treated with enzalutamide (n = 137) or apalutamide (n = 54) in the first-line setting at Jikei University Hospital or its affiliated hospitals between May 2014 and November 2022. Endpoints were defined as oncological outcomes (i.e., PSA response, PFS, PSA-PFS, MFS, CSS, and OS) and AEs. No significant differences were noted in patient backgrounds between the two groups. Patients exhibiting a maximum PSA response of >50% and >90% accounted for 74.5% and 48.9% of patients in the enzalutamide group, and 75.9% and 42.6% of patients in the apalutamide group, respectively, with no significant difference between the groups. The median PSA-PFS was 10months in the enzalutamide group but not in the apalutamide group, with no significant difference between the groups (P = 0.48). No significant differences were observed in MFS, CSS, or OS between the groups. Patients reporting AEs of all grades and grade 3 or higher accounted for 56.2% and 4.3% of those in the enzalutamide group and 57.4% and 7.4% of those in the apalutamide group, respectively. The most common AE was fatigue (26.3%) in the enzalutamide group and skin rash (27.8%) in the apalutamide group. In this retrospective study of their efficacy and safety, enzalutamide and apalutamide were shown to exhibit comparable oncological outcomes but quite different AE profiles, suggesting that their differential use may be warranted based on these findings.

A bicentric retrospective study of the correlation of EAU BCR risk groups with 18F-PSMA-1007 PET/CT detection in prostate cancer biochemical recurrence

The European Association of Urology (EAU) has proposed a risk stratification for patients harboring biochemical recurrence (BCR) after radical prostatectomy: ISUP < 4 and PSA doubling time (PSAdt) > 12 months for low risk, and ISUP ≥ 4 or PSAdt ≤ 12 months for high risk. This dual-center retrospective study aims to investigate the correlation between the EAU risk stratification for BCR following radical prostatectomy and the detection rate of lesions using 18F-PSMA-1007 PET/CT. Among the 71 included patients (58 high-risk, 13 low-risk), with a median PSA level of 1.43 ng/ml, PET/CT demonstrated a significantly higher positivity in the high-risk group compared to the low-risk group (72.4% vs. 38.0%, p = 0.026). Analysis of recurrence sites revealed a similar proportion of pelvic-confined disease in both groups (24.1% vs. 23.1%, p = 0.935), but a significantly higher incidence of metastatic disease in the high-risk group (51.7% vs. 15.4%, p = 0.017), with detailed findings indicating an increased prevalence of bone metastases in the high-risk BCR group (37.8% vs. 7.7%, p = 0.048). Therefore, PSMA PET/CT offers valuable insights for treatment decisions, aligning with the evolving landscape of prostate cancer management.

Impact of Clinical Factors on 18F-Flotufolastat Detection Rates in Men With Recurrent Prostate Cancer: Exploratory Analysis of the Phase 3 SPOTLIGHT Study

18F-Flotufolastat (18F-rhPSMA-7.3) is a newly approved prostate-specific membrane antigen targeting radiopharmaceutical for diagnostic imaging of prostate cancer (PCa). SPOTLIGHT (National Clinical Trials 04186845) evaluated 18F-flotufolastat in men with suspected PCa recurrence. Here, we present results of predefined exploratory endpoints from SPOTLIGHT to evaluate the impact of clinical factors on 18F-flotufolastat detection rates (DR). The impact of baseline prostate-specific antigen (PSA), PSA doubling time (PSAdt), and International Society of Urologic Pathology Grade Group (GG) on 18F-flotufolastat DR was evaluated among all SPOTLIGHT patients with an evaluable scan, with DR stratified according to the patients' prior treatment (radical prostatectomy ± radiation therapy [RP] or radiation therapy only [RT]). The patients underwent positron emission tomography 50 to 70 minutes after receiving 18F-flotufolastat (296 MBq IV), and scans were read by 3 blinded central readers, with the majority read representing agreement between ≥2 readers. In total, 389 men (median PSA: 1.10 ng/mL) were evaluable. By majority read, 18F-flotufolastat identified distant lesions in 39% and 43% of patients treated with prior RP or RT, respectively. The overall DR broadly increased with increasing PSA (<0.2 ng/mL: 33%; ≥10 ng/mL: 100%). Among patients with PSA <1 ng/mL, 68% had positive scans, and 27% had extrapelvic findings. PSAdt was available for 145/389 (37%) patients. PSAdt did not appear to influence 18F-flotufolastat DR (77%-90% across all PSAdt categories). Among patients with prior RP, DR ranged from 70% to 83% across PSAdt categories, and 100% DR was reported for all post-RT patients. In total, 362/389 (93%) patients had baseline GG data. Overall DRs were uniformly high (75%‒95%) across all GG. When stratified by prior treatment, DRs across all GG were 69% to 89% in patients with prior RP and ≥96% in patients with prior RT. 18F-Flotufolastat-positron emission tomography enabled the accurate detection of recurrent PCa lesions across a wide range of PSA, PSAdt, and International Society of Urologic Pathology GG, thus supporting its clinical utility for a broad range of patients with recurrent PCa.

Combination of Abiraterone Acetate, Prostate Bed Radiotherapy, and Luteinizing Hormone-releasing Hormone Agonists in Biochemically Relapsing Patients After Prostatectomy (CARLHA): A Phase 2 Clinical Trial

BackgroundThe relevance of next-generation hormone therapies and circulating tumor cells (CTCs) are not elucidated in biochemical recurrence after prostatectomy. ObjectiveTo evaluate the combination of abiraterone acetate plus prednisone (AAP), prostate bed radiotherapy (PBRT), and goserelin in biochemically relapsing men after prostatectomy, and to investigate the utility of CTCs. Design, setting, and participantsIn this single-arm multicenter phase 2 trial, 46 biochemically relapsing men were enrolled between December 2012 and January 2019. The median follow-up was 47 mo. InterventionAll patients received AAP 1000 mg daily (but 750 mg during PBRT), salvage PBRT, and goserelin. Outcome measurements and statistical analysisThe primary outcome was 3-yr biochemical recurrence-free survival (bRFS) when prostate-specific antigen (PSA) levels were ≥0.2 ng/ml. The secondary outcomes included alternative bRFS (alt-bRFS) when PSA levels were ≥0.5 ng/ml and safety assessment. CTC count was assessed. Results and limitationsThe 3-yr bRFS and alt-bRFS were 81.5% (95% confidence interval or CI [66.4–90.3%]) and 95.6% (95% CI [83.5-98.9%]), respectively. The most common acute radiotherapy-related adverse effect (AE; all grades was pollakiuria (41.3%). The most common late AE (all grades) was urinary incontinence (15.2%). Grade 3-4 acute or late radiotherapy-related AEs were scarce. Most frequent AEs nonrelated to radiotherapy were hot flashes (76%), hypertension (63%), and hepatic cytolysis (50%, of which 20% were of grades 3-4). Of the patients, 11% had a CTC count of ≥5, which was correlated with poorer bRFS (p = 0.042) and alt-bRFS (p = 0.008). The association between CTC count and higher rates of relapse was independent of the baseline PSA level and PSA doubling time (p = 0.42 and p = 0.09, respectively). This study was nonrandomized with a limited number of patients, and few clinical events were reported. ConclusionsAdding AAP to salvage radiation therapy and goserelin resulted in high bRFS and alt-bRFS. AEs remained manageable, although a close liver surveillance is advised. CTC count appears as a promising biomarker for prognosis and predicting response to treatment. Patient summaryOur study was a phase 2 clinical trial that exhibited the efficacy and tolerance of a novel androgen-receptor targeting agent (abiraterone acetate plus prednisone) in patients with prostate cancer who experienced rising prostate-specific antigen after radical prostatectomy, in combination with prostate bed radiotherapy. The results also indicated the feasibility and potential value of circulating tumor cell detection, which constitutes a possible advance in managing prostate cancers.

Salvage Reirradiation for Locally Recurrent Prostate Cancer: Results From a Prospective Study With 7.2 Years of Follow-Up.

There are no well-established re-treatment options for local recurrence after primary curative radiation therapy for prostate cancer (PCa), as prospective studies with long-term follow-up are lacking. Here, we present results from a prospective study on focal salvage reirradiation with external-beam radiation therapy with a median follow-up of 7.2 years. From 2013 to 2017, 38 patients with biopsy-proven locally recurrent PCa >2 years after previous treatment and absence of grade 2-3 toxicity from the first course of radiation were included. The treatment was 35 Gy in five fractions to the MRI-based target volume and 6 months of androgen-deprivation therapy starting 3 months before radiation. The Phoenix criteria defined biochemical recurrence-free survival (bRFS), and toxicity was scored according to Radiation Therapy Oncology Group criteria. Median age was 70 years, and median time from primary radiation to prostate-specific antigen (PSA) recurrence was 83 months. The actuarial 2-year and 5-year bRFS were 81% (95% CI, 69 to 94) and 58% (95% CI, 49 to 74), respectively. The actuarial 5-year local recurrence-free survival was 93% (95% CI, 82 to 100), metastasis-free survival was 82% (95% CI, 69 to 95), and overall survival was 87% (95% CI, 76 to 98). Two patients (5%) had durable grade 3 genitourinary toxicity, one combined with GI grade 3 toxicity. A PSA doubling time ≤6 months at salvage, a Gleason score >7, and a PSA nadir ≥0.1 ng/mL predicted a worse outcome. Reirradiation with EBRT for locally recurrent PCa after primary curative radiation therapy is clinically feasible and demonstrated a favorable outcome with acceptable toxicity in this prospective study with long-term follow-up.

Increase of prostate-specific antigen doubling time predicts survival in metastatic castration-resistant prostate cancer patients undergoing radium therapy.

Radium-223 (Ra-223) is an important treatment modality for bone-dominant metastatic castration-resistant prostate cancer (mCRPC). However, there is currently a lack of effective markers to monitor treatment response during treatment. We aim to investigate the response in prostate-specific antigen doubling time (PSADT) as a potential marker for assessing Ra-223 treatment in mCRPC patients. We retrospectively collected data from mCRPC patients who underwent radium treatment at our institution between August 2020 and June 2023. Prostate-specific antigen (PSA) measurements prior to treatment and during treatment were collected. Baseline PSADT was calculated from PSA measurements prior to Ra-223 treatment; interim PSADT was calculated from PSA measurements before Ra-223 treatment and prior to the fourth course injection. Overall survival was calculated from the start of treatment to the date of death. Univariable and multivariable analysis using the Cox proportional hazards model were performed to examine the association of factors with overall survival. We included 35 patients from our institution, with a median overall survival of 13.3months. Eighteen (51.4%) completed all six courses of treatment. PSA dynamic response (interim PSADT > baseline PSADT or decreased PSA) was observed in 20 patients. Overall survival was associated with a PSA dynamic response (HR = 0.318, 95% CI 0.133-0.762, p = 0.010) when compared to patients without response. Dynamic changes in PSADT were associated with survival in mCRPC patients receiving radium therapy. Comparing interim and baseline PSADT could serve as a valuable marker for determining treatment benefits.

The treatment landscape of nonmetastatic castrate resistant prostate cancer: A contemporary perspective

ObjectivesThe incidence of nonmetastatic castrate resistant prostate cancer (nmCRPC) is not well defined in contemporary practice. The aim of this study is to describe the incidence and patterns of treatment of nmCRPC over the last 6 years at a single high-volume Australian health institution. Subjects and methodsAll men newly diagnosed with prostate cancer at Western Health, Melbourne from January 2016 to December 2021 were included in the study. Those diagnosed with nonmetastatic prostate cancer and treated with medical or surgical castration for biochemical failure post attempted curative therapy were retrospectively reviewed for signs of castration resistance using prostate specific antigen (PSA) and testosterone biochemical markers up until October 2022. ResultsFrom January 2016 to December 2021, 822 patients were diagnosed with prostate cancer, 590 had localized disease, 373 underwent definitive locoregional therapy, and 31 went on to have biochemical recurrence and were commenced on androgen deprivation therapy. Twenty-five patients had undetectable PSA levels and were classified as having nonmetastatic castrate sensitive prostate cancer (nmCSPC), whilst the remaining 6 patients experienced a rising PSA and were thus classified as nmCRPC. The incidence rate of nmCRPC was 228 cases per 100,000 person-years.The median age at the time of prostate biopsy was 74 years (interquartile range [IQR] 64–79) in the nmCRPC group and 62 years (IQR 57–69) in the nmCSPC group. The median prebiopsy PSA (ng/ml) in the nmCRPC and nmCSPC groups were 27.5 (IQR 19.9–50.4), and 16.5 (IQR 9.0–26.0), respectively. The median duration from prostate cancer diagnosis to onset of nmCRPC was 24 months (IQR 17–29) and the median PSA doubling time was 3.4 months (IQR 2.2–5.7). ConclusionsThus, nmCRPC is an uncommon disease. Further population-based studies are required to better understand the incidence of nmCRPC.

DNA Ploidy as a Potential Adjunct Prognostic Marker of Low-Risk Prostate Cancer Progression after Radical Prostatectomy.

Post prostatectomy PSA kinetics and General Grade Groups (GGG) are the strongest prognostic markers of biochemical recurrence (BCR) and prostate cancer (PCa)-specific mortality after radical prostatectomy. Despite having low-risk PCa, some patients will experience BCR, for some, clinically significant BCR. There is a need for an objective prognostic marker at the time of prostatectomy to improve risk stratification within this population. In this study, we investigated the prognostic potential of DNA ploidy. Prostatectomy samples from 97 patients with GGG1 and GGG2 with a low-risk CAPRA-S score were included in this study. PCa tissue with the worst Gleason pattern underwent tissue disaggregation, cell isolation and staining with a DNA stoichiometric stain. Using image cytometry, DNA ploidy was measured and a Ploidy Score (PS) was generated. Among the 97 patients, 79 had no BCR, 18 experienced BCR, of which 14 had a PSA doubling time (PSA-DT) >1 year (low-risk group) and 4 had a PSA-DT of <1 year (high-risk group). Using Logistic regression analysis, only pathological T stage (pT) and PS independently predicted BCR with PS being the most significant (p = 0.001). The number of aneuploid cells was significantly higher in the high-risk group compared to the other groups (p = 1.7x10-11). PS combined with GGG diagnosis further stratified risk groups of biochemical recurrence free survival within CAPRA-S low-risk cohort. DNA ploidy is an independent prognostic marker of BCR in low-risk PCa after radical prostatectomy, which could early on identify potentially aggressive PCa recurrences and introduce a more personalized approach to salvage treatments.

Whole-body tumour burden on [18F]DCFPyL PET/CT in biochemical recurrence of prostate cancer: association with tumour biology and PSA kinetics.

The objective was to assess the association between molecular imaging (mi) variables on [18F]DCFPyL-PET/CT with clinical and disease characteristics and prostate specific antigen (PSA) related variables in patients with biochemical recurrence of prostate cancer (BRPC). We analysed patients with BRPC after radical treatment. We obtained clinical and PSA variables: International Society of Urology Pathology (ISUP) grade group, European Association of Urology (EAU) risk classification, PSA (PSA≤1ng/ml, 1<PSA≤2, PSA>2), PSA doubling time (PSAdt) and PSA velocity (PSAvel). All PET/CT scans were reviewed with the assistance of automated Prostate Molecular Imaging Standardized Evaluation (aPROMISE) software and lesions' segmentation in positive scans was performed using this platform. Standardized uptake value (SUV) derived variables; tumour burden variables [whole-body tumour volume (wbTV), whole-body tumour lesion activity (wbTLA) and whole-body mi PSMA (wbPSMA)] and miTNM staging were obtained. Cut-off of PSA and kinetics able to predict PET/CT results were obtained. Associations between disease and mi variables were analysed using ANOVA, Kruskal-Wallis and Spearman's correlation tests. Multivariate analysis was also performed. Two hundred and seventy-five patients were studied. [18F]DCFPyL-PET/CT were positive in 165/275 patients. In multivariate analysis, moment of biochemical recurrence, ISUP group, PSA level and PSAvel showed significant association with the detection rate. miTNM showed significant association with PSA level (p<0.001) and kinetics (p<0.001), being higher in patients with metastatic disease. Both PSA and PSAvel showed moderate correlation with wbTV, wbTLA and wbPSMA (p<0.001). A weak correlation with SUVs was found. Mean wbTV, wbTLA and wbPSMA values were significantly higher in PSA > 2ng/ml, PSAdt ≤ 6 months and PSAvel ≥ 0.2ng/ml/month groups. Also, wbTV (p=0.039) and wbPSMA (p=0.020) were significantly higher in patients with ISUP grade group 5. PSA and PSAvel cut-offs (1.15 ng/ml and 0.065 ng/ml/month) were significantly associated with a positive PET/CT. Higher PSA values, unfavourable PSA kinetics and ISUP grade group 5 were robust predictive variables of larger tumour burden variables on [18F]DCFPyL PET/CT assessed by aPROMISE platform.

Abstract 3813: Relationship between race/ethnicity and oncologic outcomes in patients with biochemical recurrence after primary treatment for prostate cancer

Abstract Background: Prostate cancer (PC) is the most common form of cancer in men and accounts for ~35% and 24% of all new cancer diagnoses in Black and Hispanic men, respectively. Incidence rates of PC are higher and cancer is diagnosed at a younger age in Black compared to White men. The most frequently utilized primary treatment options are radical prostatectomy (with or without adjuvant radiotherapy) or radiotherapy. Despite the success of primary treatments for localized PC, many patients (pts) will eventually develop biochemical recurrence (BCR), defined as rising prostate-specific antigen (PSA) levels. Pts with BCR are at a higher risk of developing distant metastases and ultimately dying from PC. This targeted literature review aimed to assess the real-world (RW) relationship between race/ethnicity and BCR, and further identify any differences in oncologic outcomes (risk of metastases, PC-specific mortality, and overall survival). Methods: A targeted literature search was performed using Embase, PubMed, and the past 2 years of American Society of Clinical Oncology conference proceedings. Selected studies were limited to English-language articles focusing on BCR and race or ethnicity among US populations, published between 1/2010 and 7/2023. Results: Ten studies were selected after title and abstract review. Most studies had a White pt majority (83%-92%). Six studies reported no differences in BCR or oncologic outcomes when pts were stratified by race/ethnicity. Four studies reported a higher BCR risk for Black pts with low-risk PC after radical prostatectomy, but not for pts with high-risk PC. PSA and PSA doubling time (PSADT) were found to be strong predictors of oncologic outcomes. Conclusions: The FDA draft guidance on diversity plans recommends that clinical trials enroll an adequate number of participants from underrepresented racial and ethnic populations. This requires an understanding of the diversity of the population that will eventually use the treatment and of which race/ethnicity differences in outcomes should be expected and investigated. Based on this targeted review among pts with localized PC, most RW studies had a White pt majority, and the race distribution in these studies aligned with published census and epidemiology data. In addition, findings suggest that race/ethnicity differences were not pronounced among high-risk PC pts in the US when given equal access to care or treatment, and that oncologic outcomes and BCR risk were similar across Black, White, and Hispanic pt populations. Conversely, PSA and PSADT may be stronger prognostic markers for BCR and oncologic outcomes. Future clinical trials are needed to support these RW findings and should aim to actively enroll racial/ethnic minorities to identify potential differences in efficacy and safety, and to help advance the evidence base for pt PC management. Citation Format: Nasreen Khan, Vanessa Quintero, Clara Beck, Miryana Dimova-Dobreva, Binita Patel. Relationship between race/ethnicity and oncologic outcomes in patients with biochemical recurrence after primary treatment for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3813.

Abstract 7652: Plasma markers of hemostasis, fibrinolysis, and angiogenesis prior to androgen deprivation therapy (ADT) in progressive prostate cancer (PC) and associations with long-term thrombotic events and survival

Abstract Background: PC is the third most common malignancy associated with thrombosis, procoagulants may play a role in tumorigenesis and progression, and patients (pts) with PC may have activation of the hemostatic system evident in plasma. The prognostic significance of these markers and their relationship to thrombotic events and overall survival (OS) are under-explored. Methods: Patients &amp;gt;18 years were included if they had progressive PC planned to start ADT, were &amp;gt;6 months from surgery or RT, with no history of prior VTE, unexplained bleeding, current or planned anticoagulation, or an additional active malignancy. Plasma samples were obtained via peripheral venipuncture in tubes containing 3.2% sodium citrate and immediately placed on ice. Samples were analyzed for D-dimer, thrombin-antithrombin complex (TAT), IL-6, IL-8, VEGF, and tissue factor (TF) levels by ELISA. Patients had markers drawn at baseline (prior to initiation of ADT), 1 month, and 6 months after initiation. Results: 40 patients were accrued with a median age of 68 years. At baseline, 29 (73%) had presence of metastases. Baseline median PSA was 15 and median PSA doubling time was 0.32. Baseline median hemoglobin was 13.85, platelets were 218, D-dimer was 322 ng/dL, IL-6 was 0 pg/mL, IL-8 was 0 pg/mL, TAT was 3 ug/L, VEGF was 21 pg/mL, and TF was 26 pg/mL. Median follow-up was 78 months. During follow up, 35 (87.5%) had metastases. 10 (25%) had thrombotic events (6 [15%] venous, 4 [10%] arterial) at median 37 months follow up. Median baseline age of pts with subsequent thrombotic events was 74, vs 67 in those without a thrombotic event. While there was no significant difference in baseline PSA between groups with and without clotting events, pretreatment PSA doubling time was significantly lower in pts with subsequent thrombosis (0.27 vs 0.35, p=0.047). Median baseline D-dimer and TF were higher in patients with subsequent thrombosis (D-dimer: 516 vs 282, p=0.10; TF: 36 vs 24, p=0.12). In univariate analysis, baseline IL-6 and VEGF were associated with OS (IL-6: HR=1.05, 95% CI [1.01,1.09], p=0.025; VEGF: HR=1.02, 95% CI [1.00,1.03], p=0.028). When controlling for presence of metastasis, baseline TAT was associated with OS (HR=1.05, 95% CI [1.00,1.11], p=0.055). Conclusions: Plasma markers of hemostatic activation, fibrinolysis, and angiogenesis prior to initiation of ADT are associated with subsequent thrombotic events and overall survival years later. Further analysis will examine how these markers change over time with hormonal therapy. Citation Format: Jessica S. Palmer, Charlene Thomas, Nicole Jacobs, David Nanus, Scott T. Tagawa. Plasma markers of hemostasis, fibrinolysis, and angiogenesis prior to androgen deprivation therapy (ADT) in progressive prostate cancer (PC) and associations with long-term thrombotic events and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7652.

Metastases-directed radiotherapy in castration resistant oligo metastatic prostate cancer: A multicentric retrospective study from the French group COLib

Oligometastases aredefined as a number of detectable metastases less or equal to 5. In castrate-resistant oligo metastatic prostate Cancer (CR oligoM PC), Metastases-Directed Ablative radiotherapy (MDRT) is poorly investigated. Our study retrospectively reviewed the cases of CR oligoM PC treated with MDRT in 8 French high-volume radiotherapy centers.OS and PFS are defined as the delay between the first day of MDRT and death (OS) or progression according to PCWG criteria (PFS). OS and PFS are evaluated according to Kaplan Meyer, curves are compared with log rank test. Logistic regression was used to identify predictive factors for outcome: bone versus node metastasis, ISUP grade, PSA doubling Time (PSADT) at the time of MDRT, time to castration resistance.107 patients were included in the study, among those 197 metastases received MDRT. For the overall population, the median follow-up was 25.2 months (1,4–145). OS was 93 % at 2 years and 81,4% at 3 years. At 2 years, 100 % of patients with node-only metastasis were alive versus 88,7% among those who have bone metastases (p = 0,72). The median PFS was 12,6 months (IC 95 % [9,6; 17]), with no difference among patients with node only disease versus the rest of the cohort.The PFS was 18,2 months (10,0; 32,4) in patients with PSADT >6 months versus 10,7 months (8,9; 14,3) when PSADT was inferior to 6 months. However, this difference did not reach significant.We did not find a correlation neither between ISUP grade (1–2 versus 3–4-5) and PFS, nor between hormone-sensitivity duration and PFS.Patients receiving MDRT for CR oligoM PC have a good prognosis with 81,6% OS at 3 years. PSA DT longer than 6 months could be related to better PFS. MDRT strategy could postpone the onset of new systemic treatment with median PFS >1 year.

A Phase II Study of Rucaparib Monotherapy in Nonmetastatic, Hormone-Sensitive Prostate Cancer Demonstrating "BRCAness" Genotype (ROAR).

Both germline and somatic BReast CAncer gene (BRCA) mutations are poor prognostic markers in men with localized or metastatic prostate cancer. For instance, men with these mutations often are diagnosed with prostate cancer earlier and develop metastatic disease earlier compared with those who do not harbor similar mutations. Patients with germline alterations typically have more advanced disease and shorter overall survival (Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882). The risk of disease progression to metastatic disease is significant in patients with this genotype of prostate cancer. The percentage of patients free from metastatic disease was 90%, 72%, and 50%, respectively, compared with 97%, 94%, and 84% at 3, 5, and 10 years for patients with intact DNA repair (P < .001) (Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022). DNA damage repair non-BRCA mutations include alterations in genes such as ATM, CHEK2, PALB2, and RAD51. While less common than BRCA mutations, they have emerged as significant prognostic markers in prostate cancer. These BRCAness mutations are associated with a higher risk of aggressive disease and poorer survival outcomes. Given the debilitating physical and psychological side effects of androgen deprivation therapy (ADT) in relatively younger men with prostate cancer, delaying ADT in these men may be an attractive strategy. Given the proven efficacy of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the castration-resistant prostate cancersetting, PARP inhibitor monotherapy in a nonmetastatic castration-sensitive (nmCSPC) setting has the potential to delay metastasis and delay the onset of ADT related symptoms. This is a single-arm, single-center, open-label, phase II trial to assess the efficacy of rucaparib in patients with high-risk biochemically recurrent (BCR) nmHSPC, which was defined as PSA doubling time of <9 months, demonstrating a "BRCAness" genotype (BRCA1/2 and other homologous recombination repair mutations). A total of 15 patients were intended to be enrolled, with an expected enrollment duration of 12 months. Patients were given rucaparib 600 mg orally twice daily and were allowed to remain on study treatment until PSA progression defined by Prostate Cancer Working Group 3, with 2 years of follow-up after study treatment. We anticipated a total of 2-3 years until completion of the clinical trial. The primary endpoint was to assess the PSA progression-free survival (PSA-PFS). The secondary endpoints of the study were safety, the proportion of patients with a PSA 50% response (PSA 50), and an undetectable PSA. A 4-week treatment duration comprised one cycle. The study started enrolling in June 2019 and was prematurely terminated in June 2022 after the accrual of 7 patients because of changing standard of care treatments with the introduction of next-generation scans, eg, prostate-specific membrane antigen positron emission tomography (PSMA-PET). Seven patients were enrolled in the study with the following pathogenic alterations: ATM (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), BRIP1 (n = 1), and RAD51 (n = 1). 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). In total, 2 patients achieved PSA50; both also achieved nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 patient each). No dose-limiting toxicities or severe AEs were seen. Rucaparib demonstrated acceptable toxicity and efficacy signal as an ADT-sparing approach in patients with biochemically recurrent nonmetastatic prostate cancer. It is currently challenging to understand the optimal value of systemic therapy in this disease setting due to the rapidly changing standard of care. Additionally, there are relatively few patients with BRCAness who present with nonmetastatic hormone-sensitive prostate cancer (ClinicalTrials.gov Identifier: NCT03533946).

Prognostic Value of the Modeled Prostate-Specific Antigen KELIM Confirmation in Metastatic Castration-Resistant Prostate Cancer Treated With Taxanes in FIRSTANA.

In a previous exploratory study, modeled early longitudinal prostate-specific antigen (PSA) kinetics observed within the 100-first treatment days with androgen deprivation therapy with or without docetaxel was associated with progression-free survival (PFS) and overall survival (OS) in patients with prostate cancer with rising PSA levels after primary local therapy. This prognostic value had to be confirmed in different settings. The objectives were to assess PSA kinetics modeling in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with chemotherapy in FIRSTANA trial and to investigate modeled PSA kinetic parameters prognostic/predictive value. FIRSTANA phase III trial (ClinicalTrials.gov identifier: NCT01308567) assessed whether cabazitaxel is superior to docetaxel in terms of PFS/OS in patients with chemotherapy-naïve mCRPC. PSA longitudinal kinetics was assessed using the previous kinetic-pharmacodynamics model. Patient modeled ELIMination rate constant K (PSA.KELIM) was used to categorize favorable/unfavorable PSA declines (standardized PSA.KELIM < or ≥ 1.0 days-1) and further correlated with PFS/OS. In total, 1,050 of 1,168 enrolled patients were assessable for PSA.KELIM estimation. The median PSA.KELIM was 0.02 days-1. In univariate analyses, PSA.KELIM exhibited a significant prognostic value regarding survival: unfavorable versus favorable PSA.KELIM; median PFS, 3.6 months (95% CI, 3.0 to 4.2) versus 4.7 months (95% CI, 3.9 to 5.2), P = .002; median OS, 17.4 months (95% CI, 14.8 to 19.3) versus 28.4 months (95% CI, 26.7 to 31.6), P < .001. In multivariate analyses, PSA.KELIM was significant for PFS (hazard ratio [HR], 0.79 [95% CI, 0.67 to 0.93], P = .005) and OS (HR, 0.51 [95% CI, 0.44 to 0.60], P < .001), together with baseline radiological tumor progression and PSA doubling time. PSA.KELIM predictive value was not significant across treatment arms. This external validation study confirmed previous results about modeled PSA longitudinal kinetics prognostic value regarding PFS/OS in patients with mCRPC treated with taxanes. PSA.KELIM could be used to identify a subpopulation with poor prognosis, who may benefit from treatment intensification.

High-intensity interval training versus moderate-intensity continuous training for localized prostate cancer under active surveillance: a systematic review and network meta-analysis.

High-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) have been increasingly adopted for localized prostate cancer (PCa) under active surveillance (AS). However, it is unclear which training modality is the most favorable in terms of cardiorespiratory fitness and biochemical progression. We searched PubMed, Cochrane and Embase for relevant RCTs. PRISMA guideline was adopted to ensure optimal conduct of this study. Serum prostate specific antigen (PSA) and peak VO2 were selected as primary outcomes and PSA doubling time (PSADT) and testosterone were selected as secondary outcomes. Only articles written in English were included. Cochrane risk-of-bias tool was used for risk of bias evaluation. A total of 501 studies were selected. Six RCTs with 222 patients were included for data extraction and analysis. High-intensity interval training (HIIT) group demonstrated significantly lower PSA compared with usual care (UC) (MD = -1.4; 95%CI = -2.77 to -0.03) and moderate-intensity continuous training (MICT) group (MD = -1.67; 95%CI = -3.30 to -0.05). Both HIIT and MICT showed significantly improved peak VO2 compared with UC. No significant difference was observed in PSADT and testosterone among different training modalities and UC. Regarding peak VO2, MICT had the highest surface under cumulative ranking curve (SUCRA) scores (98.1%). For serum PSA, HIIT had the highest probability (97.8%) to be the training with the highest efficacy. The potential source of bias mainly came from poorly performed allocation concealment and blinding strategies. The present study indicated that HIIT and MICT showed considerable cardiorespiratory benefits for localized PCa. HIIT was preferred over MICT in biochemical progression control in terms of decreasing serum PSA levels. However, MICT was favored over HIIT regarding cardiorespiratory benefits. The findings of this study may facilitate future lifestyle intervention, particularly in the form of physical training, for individuals diagnosed with localized PCa under AS.

What criteria do clinicians use to classify men as “high risk” among patients with biochemically recurrent nonmetastatic castration-sensitive prostate cancer?

300 Background: In patients with biochemically recurrent (BCR) nonmetastatic castration-sensitive prostate cancer (nmCSPC), guidelines support the use of clinical factors such as prostate-specific antigen doubling time (PSADT) and Gleason score to identify high-risk patients who are more likely to develop metastases and could benefit from earlier intervention. The current study aimed to understand criteria used by physicians in the real-world to categorize patients with BCR nmCSPC as high-risk. Methods: This analysis used data from the Adelphi Real World nmCSPC retrospective survey, completed by urologists and radiation oncologists in the US. Physicians extracted data from medical charts for their last 6–8 patients diagnosed with high-risk BCR nmCSPC since January 2021 (until July 2023). A physician attitudinal survey was also completed. Data were analyzed descriptively. Results: Overall, 84 physicians provided data (68 urologists; 16 radiation oncologists). When asked in general (not patient specific) to name clinical factors used to determine level of risk, physicians cited using multiple factors, most frequently PSADT (93%), Gleason score (88%), absolute PSA rise following definitive therapy (86%), and clinical stage (85%). PSADT was cited as the single most important clinical factor by nearly 50%, followed by Gleason score, clinical stage, and absolute PSA rise following definitive therapy (Table). For physicians who used PSADT to risk stratify, the median (IQR) threshold for high-risk was 6 (6–9) months. Aggregated patient-level data were analyzed for 352 patients with high-risk BCR nmCSPC, as defined by the physicians. Clinical factors used to classify patients as having high-risk BCR in this study included PSADT (58%), Gleason score (44%), absolute PSA rise after definitive therapy (42%), clinical stage (21%), and pathological findings at radical prostatectomy (15%). Overall, 65% of patients had a PSADT ≤9 months after BCR, and 68% had a PSADT &lt; 12 months (high-risk per the AUA guidelines). Conclusions: Physicians reported using multiple clinical factors to classify patients as having high-risk BCR nmCSPC, with PSADT considered the most important for risk stratification. Appropriate and timely identification of patients as high-risk may help to identify patients for whom earlier intervention could be beneficial.[Table: see text]

Outcomes of men with high-risk biochemically recurrent prostate cancer who suspended enzalutamide monotherapy treatment in the phase 3 EMBARK study.

15 Background: In the 3-arm EMBARK trial, enzalutamide (enza) + leuprolide acetate (leuprolide) and enza monotherapy (mono) showed statistically superior and clinically meaningful improvements in metastasis-free survival (MFS) vs placebo + leuprolide (alone) in patients (pts) with high-risk biochemically recurrent (BCR) prostate cancer. Based on serum prostate-specific antigen (PSA) response, treatment (tx) was suspended at week 37 in 304 (85.9%) pts in the enza mono arm and 240 (67.8%) in the leuprolide-alone arm; pts who did not meet suspension criteria continued tx. Outcomes with enza mono vs leuprolide alone by tx suspension status are presented. Methods: EMBARK is a double-blind phase 3 study of pts with high-risk BCR (i.e., PSA doubling time (PSADT) ≤9 months and PSA ≥2 ng/mL above nadir post-radiotherapy [RT] or ≥1 ng/mL after radical prostatectomy [RP] ± postoperative RT). Pts were randomized (1:1) to enza mono (160 mg/day, open-label) or leuprolide alone (22.5 mg every 12 weeks). PSA &lt;0.2 ng/mL at week 36 triggered tx suspension at week 37; tx restarted when PSA reached ≥2 ng/mL or ≥5 ng/mL for pts with or without primary RP, respectively. The proportion of pts with undetectable PSA 2 years after tx suspension was a secondary endpoint. MFS (by blinded independent central review) was analyzed descriptively in each tx arm by suspension status. P-values were nominal. Results: In the suspension group, the 3-year MFS rate (95% CI) was 88.1% (83.8–91.4%) for enza mono and 90.0% (85.3–93.2%) for leuprolide alone; there was no difference in MFS (hazard ratio [HR] 0.840, 95% CI 0.575–1.226; P=0.3659). In the no suspension group, 3-year MFS rates were 88.5% (68.5–96.2%) and 66.9% (55.4–76.1%), respectively; MFS was longer with enza mono vs leuprolide alone (HR 0.340, 95% CI 0.118–0.985; P=0.0378). In the suspension group vs the no suspension group, a greater proportion had received prior RP (enza mono: 78.9 vs 41.9%; leuprolide alone: 78.3 vs 52.2%) or RP and RT (enza mono: 50.7 vs 16.1%; leuprolide alone: 55.0 vs 38.0%), while baseline median PSADT was similar (enza mono: 4.9 vs 5.9 months; leuprolide alone: 5.0 vs 4.8 months). The proportion (95% CI) of pts with undetectable PSA 2 years after tx suspension was 4.6% (2.5–7.6%) for enza mono and 9.6% (6.2–14.0%) for leuprolide alone ( P=0.0326). Conclusions: In pts with high-risk BCR who suspended tx, the tx effect on MFS with enza mono was not different compared with leuprolide alone, though more pts reached tx suspension criteria with enza mono. However, in the no suspension group, enza mono prolonged MFS vs leuprolide alone, though the number of MFS events was limited (n=4). Pts with prior RP were also more likely to reach the PSA threshold for tx suspension. Few pts who suspended tx had undetectable PSA after 2 years, regardless of tx. Clinical trial information: NCT02319837 .

Real-world treatment patterns for patients with high-risk biochemically recurrent nonmetastatic castration-sensitive prostate cancer.

299 Background: Patients with biochemically recurrent (BCR) nonmetastatic castration-sensitive prostate cancer (nmCSPC) who are identified as high-risk of developing metastases may benefit from earlier treatment. This study analyzed treatment patterns in these patients. Methods: The Adelphi Real World nmCSPC retrospective survey was completed by urologists and radiation oncologists in the US. For this analysis, data from medical charts for patients diagnosed with high-risk BCR nmCSPC from Jan 2021–Jul 2023 were extracted; physicians completed a chart for their last 6–8 patients. Data were analyzed descriptively for first line (1L) treatment received (regardless of time) since high-risk BCR diagnosis for the total patient sample and subgroups of interest. Physicians documented those with no treatment as on observation. Results: Aggregated data were analyzed for 376 patients with high-risk BCR nmCSPC; 252 (67%) had prostate-specific antigen doubling time (PSADT) ≤9 months after BCR and initial definitive therapy of radiotherapy (RT) and/or radical prostatectomy (RP). Overall, 84% were treated by urologists and 16% by radiation oncologists. Median age was 70 years; 64% were White, 31% were Black/African American. Median PSA at high-risk BCR diagnosis was 5 ng/mL. Median follow-up after high-risk BCR diagnosis was 249 days. Median time between high-risk BCR diagnosis and initiation of 1L treatment was 17 days. Most common 1L treatments were androgen deprivation therapy (ADT) alone, salvage RT, novel hormonal therapy (NHT) + ADT, and observation alone. For patients on observation alone, median follow-up after high-risk BCR diagnosis was 181 days. Few numerical differences were seen in treatment patterns depending on how patients were determined as high-risk (Table). Patients treated by urologists rather than radiation oncologists had numerically higher proportions of 1L treatment with NHT + ADT (21% / 2%) and observation alone (17% / 8%), and numerically lower proportions of ADT alone (27% / 34%) and salvage RT (12% / 44%). Conclusions: First line treatments were typically initiated rapidly following high-risk BCR nmCSPC diagnosis, with only 15% of patients receiving observation alone during available follow-up. [Table: see text]

EMBARK post hoc analysis of sexual activity (SA) patient-reported outcome (PRO) measures.

313 Background: In the phase 3 EMBARK trial (NCT02319837), enzalutamide (ENZ) + leuprolide (L) and ENZ monotherapy (mono) delayed metastasis-free survival (MFS) vs placebo (P) + L without impairing global health-related quality of life (HRQoL) in high-risk biochemically recurrent (BCR) nonmetastatic hormone-sensitive prostate cancer (nmHSPC) (PSA doubling time ≤9 months). A prespecified PRO analysis showed that SA (measured as a composite score using European Organization for Research and Treatment of Cancer QoL Questionnaire-Prostate 25 [QLQ-PR25]) was better preserved with ENZ mono vs P + L and no significant difference between ENZ + L vs P + L. A post hoc analysis at the HRQoL item level was conducted to understand the effect on SA in each comparison and enable shared decision-making between physicians and patients. Methods: Men with high-risk BCR nmHSPC were randomized (1:1:1) to ENZ + L (double blind), ENZ mono (open label), and P + L (double blind). HRQoL was assessed at baseline and every 12 weeks until metastasis/death. This post hoc analysis assessed effects on time to confirmed (two consecutive visits) deterioration (TTCD) using predefined thresholds of one category decline from baseline in sexual interest, activity, satisfaction, erectile function, and feeling like a man using QLQ-PR25 item 50; QLQ-PR25 item 51; FACT-P item GS7; FACT-P item BL5; and FACT-P item P5 measures, respectively (Table). Intent-to-treat principle was applied. Results: At baseline, 327–332 men per arm completed the PRO surveys; overall completion rates were ≥85%, except for GS7 (≤36% due to voluntary response). ENZ mono vs P + L : TTCD in items 50 (interest) and 51 (activity), GS7 (satisfaction), and BL5 (erectile function) was delayed with ENZ mono. ENZ + L vs P + L: no significant differences in TTCD were observed, except a shorter TTCD by a median 0.06 months in BL5 (erectile function) with ENZ + L (Table). Conclusions: This post hoc item-level analysis of the EMBARK trial confirmed that SA was better preserved with ENZ mono vs P + L in terms of interest, activity, satisfaction, and maintaining erection. Further, the SA PROs were similar between ENZ + L and P + L, implying there is no further SA burden when adding ENZ to androgen-deprivation therapy. Clinical trial information: NCT02319837 . [Table: see text]

Salvage Radiotherapy for Relapsed Prostate Cancer after Radical Prostatectomy Is Associated with Normal Life Expectancy

In patients with prostate cancer (PCa), salvage radiotherapy (SRT) for biochemical progression (BP) after radical prostatectomy (RP) improves PCa-specific survival. However, no prospective randomized trials have compared the effect of SRT with untreated patients. In this analysis of 151 patients who received SRT for post-RP BP, we compared their overall survival (OS) with virtual, age-matched controls (n = 151,000) retrieved from government life tables. We also investigated the risk factors associated with BP and OS and compared the prostate-specific antigen (PSA) doubling times (DTs) before and after SRT for patients with BP. The median follow-up was 9.3 years for BP and 17.4 years for OS. The risk factors significantly affecting BP were Gleason score (p &lt; 0.001), pre-SRT PSA (p = 0.003), and negative surgical margins (p = 0.003). None of these risk factors were associated with OS. In 93 patients with BP after SRT, the median PSADT was significantly prolonged compared with pre-SRT values (3.7 vs. 8.3 months, p &lt; 0.001). The OS did not differ between patients and controls (p = 0.112), and life expectancy was similar, likely due to the survival benefit of SRT. The prolonged PSADT after SRT further supports the beneficial role of SRT in this patient population. However, subsequent treatments were not systematically recorded, which may have affected the results.