High-risk Nonmetastatic Prostate Cancer Research Articles

Overall survival benefit of androgen suppression in addition to dose-escalated external beam radiotherapy for high-risk prostate cancer: Nationwide real-world data indicates a shift in men that benefit

ObjectiveTo evaluate the real-world added value of androgen deprivation therapy (ADT) in addition to external beam radiotherapy (EBRT) in men with high-risk non-metastatic prostate cancer, in view of advances in radiotherapy and diagnostics. MethodsAll Dutch men diagnosed with high-risk non-metastatic prostate cancer (defined as: ≥cT2c-T3b N0M0, PSA ≥20–50 ng/ml, and/or Gleason score ≥8 (International Society of Urological Pathology [ISUP] grade ≥4)) from 2009 through 2019 and treated with EBRT with or without ADT were identified in the population-based Netherlands Cancer Registry.Propensity scores were used to match (1:1) men that received ADT to men that did not receive ADT. Subsequently, OS was compared. Analyses were also stratified by number of high-risk features, 1 (either ≥cT2c, PSA >20 ng/ml or Gleason score ≥8) versus ≥2 (out of ≥cT2c, PSA >20 ng/ml and Gleason score ≥8). ResultsA total of 14,773 men with high-risk non-metastatic prostate cancer were identified, 3,958 (27%) of which received EBRT alone. After matching, 3,427 men remained in both groups and baseline characteristics were well-balanced. After a median follow-up of 92 months, OS was better in men treated with EBRT and ADT compared to men treated with EBRT alone (10-year OS: 66.4% versus 61.8%; HR 0.88 [95%CI: 0.80–0.96]). There was no statistically significant difference in OS in the subgroup of men with only 1 high-risk feature (10-year OS 67.7% versus 64.9%; HR 0.95 [95%CI: 0.85–1.07]). ConclusionsIn a contemporary cohort of men treated for high-risk non-metastatic prostate cancer with EBRT, an OS benefit of adding ADT was only observed in men with at least 2 high-risk features. These results suggest that improvements in diagnostics and treatment in recent decades have resulted in a stage shift of men benefiting from the addition of ADT to EBRT.

Abstract 4570: Prostate-specific membrane antigen targeted chemo-photodynamic therapy for the treatment of prostate cancer

Abstract Introduction: Prostate cancer is the most prevalent cancer among men in the United States and is their second leading cause of cancer death. During initial screen, about 17-31% of patients are diagnosed with non-metastatic high-risk localized prostate cancer. These patients have an increased risk of treatment failure and oncological progression. The contemporary treatment paradigm of high risk localized prostate cancer is moving toward a multidisciplinary integrated approach of systemic and local therapy. In addition, incorporation of molecular biomarkers can also improve the risk stratification and treatment of prostate cancer. Among the biomarkers for prostate cancer, prostate specific membrane antigen (PSMA) has been proven to be an excellent target for diagnosis and treatment of prostate cancer. We have generated a PSMA-targeted photodynamic therapy (PDT) agent, PSMA-1-Pc413, and a PSMA-targeted chemotherapeutic agent, PSMA-1-MMAE. The objective of this study is to generate a new molecule that combines PDT and chemotherapy to achieve improved antitumor activity. Methods: Using a bifunctional PSMA ligand, a novel theranostic PSMA-targeting conjugate was synthesized, which integrated both the photosensitizer Pc413 and the microtubular inhibitor monomethyl auristatin E (MMAE) in one simple molecule, PSMA-1-MMAE-Pc413. This molecule was first tested for in vitro uptake and cytotoxicity studies using PSMA-positive PC3pip and PSMA-negative PC3flu cells. The conjugate was then tested for in vivo fluorescence imaging using mice bearing both PC3pip and PC3flu tumors. Finally, the antitumor activity of PSMA-1-MMAE-Pc413 was tested in mice with PC3pip tumors with and without light irradiation. Results: In in vitro uptake studies, the uptake of PSMA-1-MMAE-Pc413 in PC3pip tumor was about 3-fold higher than that in PC3flu cells. In in vitro cytotoxicity studies, when exposed to 5 J/cm2 of 672nm light, PSMA-1-MMAE-Pc413 demonstrated a synergistic effect leading to greater cytotoxicity for PC3pip cells (IC50=2.77nM) when compared to PSMA-1-Pc413 with light irradiation (IC50=372nM) or PSMA-1-MMAE-Pc413 without light irradiation (IC50=12.6nM). In in vivo imaging studies, PSMA-1-MMAE-Pc413 demonstrated selective uptake in PC3pip tumors. Further, antitumor activity studies showed that PSMA-1-MMAE-Pc413 with light irradiation significantly inhibited PC3pip tumor growth and prolonged survival time as compared to mice receiving equimolar amounts of PSMA-1-Pc413 with light irradiation or PSMA-1-MMAE-Pc413 without light irradiation. Conclusion: We have synthesized a new theranostic agent PSMA-1-MMAE-Pc413 that combines imaging, chemotherapy and PDT. The new molecule dramatically improves the treatment effect as compared to each single treatment alone. (The work is supported by NIH 1RO1CA255925-01A.) Citation Format: Xinning Wang, Aditi Shirke, Sriprada Chavali, Lifang Zhang, Ethan Walker, Gopolakrishnan Ramamurthy, James Basilion. Prostate-specific membrane antigen targeted chemo-photodynamic therapy for the treatment of 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 4570.

Time trends in the use of curative treatment in men 70 years and older with nonmetastatic prostate cancer.

Undertreatment of otherwise healthy men in their seventies with prostate cancer has been reported previously. Using information in a Swedish prostate cancer research database, patterns of management and cancer-specific mortality were compared across age groups in over 70,000 men diagnosed with intermediate- or high-risk nonmetastatic prostate cancer between 2008 and 2020. Crude probabilities of death were estimated non-parametrically. Staging procedures, primary treatment, and cancer death were compared using regression models, adjusting for patient and tumor characteristics. During the study period, the proportion of men treated with curative intent increased in ages 70-74 (intermediate-risk from 45% to 72% and high-risk from 49% to 84%), 75-79 (intermediate-risk from 11% to 52% and high-risk from 12% to 70%), and 80-84 years (intermediate-risk from < 1% to 14% and high-risk from < 1% to 30%). Older age was associated with lower likelihoods of staging investigations and curative treatment, also after adjustment for tumor characteristics and comorbidity. Men treated with curative intent and those initially managed conservatively had lower crude risks of prostate cancer death than men receiving androgen deprivation treatment (ADT). In adjusted analyses, ADT was associated with higher prostate cancer mortality than curative treatment across ages and risk groups. Among men managed conservatively, prostate cancer mortality was higher in ages 70 and above. Use of curative treatment increased substantially in older men with prostate cancer between 2008 and 2020. Our findings suggest reduced age-bias and under-treatment, likely reflecting improved individualized decision-making and adherence to guidelines recommending more active management of older men.

Protocol of a randomised, controlled trial comparing immediate curative therapy with conservative treatment in men aged ≥75 years with non-metastatic high-risk prostate cancer (SPCG 19/GRand-P).

Older men (aged ≥75 years) with high risk, non-metastatic prostate cancer (PCa) are increasingly treated with curative therapy (surgery or radiotherapy). However, it is unclear if curative therapy prolongs life and improves health-related quality of life (HRQoL) in this age group compared to conservative therapy, which has evolved considerably during the last decade. The Scandinavian Prostate Cancer Group (SPCG) 19/Norwegian Get-Randomized Research Group-Prostate (GRand-P) is a randomised, two-armed, controlled, multicentre, phase III trial carried out at study centres in Norway, Denmark, Finland, and Sweden. The primary endpoints are overall survival and HRQoL (burden of disease scale, European Organisation for the Research and Treatment of Cancer [EORTC] Elderly Cancer patients). Secondary endpoints are PCa-specific survival, metastasis-free survival, role-functioning scale (EORTC quality of life questionnaire 30-item core), urinary irritative/obstructive scale (26-item Expanded Prostate Cancer Index Composite [EPIC-26]), bowel scale (EPIC-26), intervention-free survival, PCa morbidity, use of secondary and tertiary systemic therapies, mean quality-adjusted life-years (QALYs), and mean total healthcare costs. A total of 980 men (aged ≥75 years) with non-metastatic, high-risk PCa will initially be screened with Geriatric 8 (G8) health status screening tool and Mini-COG© brief cognitive test. Participants identified by G8 as 'fit' or 'frail' will be randomised (ratio 1:1) to either immediate curative therapy (radiotherapy or prostatectomy) or conservative therapy (endocrine therapy or observation). Participants who are unable or unwilling to participate in randomisation will be enrolled in a separate observation group. Randomised patients will be followed for 10 years. Ethics approval has been granted in Norway (457593), Denmark (H-22051998), Finland (R23043) and Sweden (Dnr 2023-05296-01). The trial is registered on Clinicaltrials.org (NCT05448547).

Improving the identification of high-risk non-metastatic castration-resistant prostate cancer patients in clinical practice.

Non-metastatic castration-resistant prostate cancer (nmCRPC) represents a challenging disease state in prostate cancer care. nmCRPC patients with a high risk of progression to metastatic disease who are identified by a prostate-specific antigen doubling time (PSADT) ≤10 months are eligible for treatment with the novel androgen receptor inhibitors (ARIs), shown to delay disease progression and extend survival. However, nmCRPC is often unexploited in clinical practice due to a lack of standardization in the methodology and in the tools used for its identification. In this article, a group of Urology and Oncology specialists with acknowledged expertise in prostate cancer reviews the state of the art in the management of high-risk nmCRPC patients, identifies gaps and unmet needs, and proposes strategies to optimize the identification of this patient subgroup in the clinical practice and improve their health outcomes.

Very Long-Term Complete Remission Can Be Achieved in Men With High-Risk Localized Prostate Cancer and a Very High PSA Value: An Analysis of the GETUG 12 Phase 3 Trial.

Serum prostate specific antigen (PSA) is a well-known prognostic parameter in men with prostate cancer. The treatment of men with very high PSA values and apparently no detectable metastases is not fully established. Ancillary analysis from the GETUG 12 phase 3 trial. Patients with non-metastatic high-risk prostate cancer by bone and computerized tomography (CT) scan were randomly assigned to receive androgen deprivation therapy (ADT) and docetaxel plus estramustine or ADT alone. Relapse-free survival (RFS), clinical RFS, metastases-free survival (MFS), overall survival (OS), and prostate cancer-specific survival (PCSS) were estimated using the Kaplan-Meier method for different levels of PSA (50 ng/mL, 75 ng/mL, and 100 ng/mL). The relationship between PSA and outcomes was studied using residual-based approaches and spline functions. The median follow-up was 12 years (range: 0-15.3). Baseline PSA (<50 ng/mL, n=328; ≥50ng/mL, n=85) was associated with improved RFS (P=.0005), cRFS (P=.0024), and MFS (P=.0068). The 12-year RFS rate was 46.33% (CI 40.59-51.86), 33.59% (CI 22.55-44.97), and 11.76% (1.96-31.20) in men with PSA values <50 ng/mL (n=328), 50-100 ng/mL (n=68), and ≥100 ng/mL (n=17), respectively. Exploratory analyses revealed no deviation from the linear relationship assumption between PSA and the log hazard of events. Men with apparently localized prostate cancer and a high baseline PSA value have a reasonable chance of being long-term disease-free when treated with curative intent combining systemic and local therapy.

The diagnostic accuracy of 68 Ga-PSMA-PET/CT in primary staging of patients with high-risk nonmetastatic prostate cancer treated with radical prostatectomy: A single-center cohort analysis.

68 Ga-prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography(CT) is a recommended imaging modality for patients with recurrent prostate cancer (PCa). Its routine implementation before radical prostatectomy (RP) may allow avoiding undertreatment. We aimed to analyze the diagnostic accuracy of 68 Ga-PSMA-PET/CT for pelvic lymph node metastases in a large cohort of patients treated with RP and extended pelvic lymph node dissection (ePLND) for high-risk PCa. This is a retrospective analysis of an institutional database of patients who underwent 68 Ga-PSMA-PET/CT before RP and ePLND for high-risk PCa. The diagnostic estimates of 68 Ga-PSMA-PET/CT with 95% confidence intervals (CIs) for lymph node involvement were calculated. We included 165 high-risk PCa patients. The median PSA value was 24.5 ng/mL (range: 6.7-185) and all the patients had biopsy Grade Group 4-5. In total, 46 (28%) of patients had clinical lymph node involvement at 68 Ga-PSMA-PET/CT. A mean number of resected lymph nodes per patient was 22 (range: 15-45) and 149 (4.2%) of all resected nodes were positive for lymph node metastasis at final pathology. The diagnostic estimates for the detection of pN+ disease at RP were as follows: sensitivity 63% (95% CI: 51-75), specificity 97% (95% CI: 91-99), positive predictive value 94% (95% CI: 82-99), and negative predictive value 79% (95% CI: 70-86). The total accuracy of PSMA-PET was 83% (95% CI: 76-88). Our analyses support high specificity and positive predictive value of pretreatment 68 Ga-PSMA PET/CT for the detection of pelvic lymph node metastasis in patients treated with RP for high-risk PCa. While a positive finding should be considered as robust indicator for clinical decision-making, a negative result cannot reliably rule out the presence of lymph node involvement in high-risk PCa; there is a need for advanced risk stratification in those patients.

Impact of performance status on efficacy of systemic therapy for prostate cancer: a meta-analysis.

To evaluate the efficacy of systemic therapies in patients with worse performance status (PS) treated for high-risk non-metastatic prostate cancer (PCa), metastatic hormone-sensitive PCa (mHSPC), and non-metastatic/metastatic castration-resistant PCa (nmCRPC/mCRPC), as there is sparse pooled data showing the effect of PS on oncological outcomes in patients with PCa. Three databases were queried in June 2022 for randomised controlled trials (RCTs) analysing patients with PCa treated with systemic therapy (i.e., adding androgen receptor signalling inhibitor [ARSI] or docetaxel [DOC] to androgen-deprivation therapy [ADT]). We analysed the oncological outcomes of patients with PCa with worse PS, defined as Eastern Cooperative Oncology Group PS ≥ 1, treated with combination therapies and compared these to patients with good PS. The main outcomes of interest were overall survival (OS), metastasis-free survival (MFS), and progression-free survival. Overall, 25 and 18 RCTs were included for systematic review and meta-analyses/network meta-analyses, respectively. In all clinical settings, combination systemic therapies significantly improved OS in patients with worse PS as well as in those with good PS, while the MFS benefit from ARSI in the nmCRPC setting was more pronounced in patients with good PS than in those with worse PS (P = 0.002). Analysis of treatment ranking in patients with mHSPC revealed that triplet therapy had the highest likelihood of improved OS irrespective of PS; specifically, adding darolutamide to DOC + ADT had the highest likelihood of improved OS in patients with worse PS. Analyses were limited by the small proportion of patients with a PS ≥ 1 (19%-28%) and that the number of PS 2 was rarely reported. Among RCTs, novel systemic therapies seem to benefit the OS of patients with PCa irrespective of PS. Our findings suggest that worse PS should not discourage treatment intensification across all disease stages.

PSMA PET findings in an “EMBARK-like” cohort of patients with high-risk non-metastatic hormone-sensitive prostate cancer: A single center post-hoc retrospective analysis.

5091 Background: The EMBARK trial is a phase 3, randomized, study evaluating use of enzalutamide with or without concomitant leuprolide in non-metastatic castrate sensitive prostate cancer patients. Eligibility status for the trial relied upon conventional imaging which under detects metastatic disease in comparison to PSMA-PET imaging. The aim of this post-hoc retrospective analysis was to describe the PSMA-PET findings in a patient population representative of the EMBARK trial. Methods: This was a post-hoc, retrospective analysis of 5 prospective studies of PSMA PET conducted at UCLA from 2016 to 2021 that included patients with recurrent PCa following RP, RT or SRT. Patients were included if they met eligibility for enrollment in the EMBARK trial at the time of their PSMA scan defined as the following: Rising PSA at a level above 1.0ng/mL (post RP and SRT) or 2.0ng/mL &gt; nadir (post-RT), PSA doubling time ≤ 9 months, Serum testosterone ≥ 150 ng/dL. Exclusion criteria constituted: distant metastatic disease as assessed by radiographic imaging, prior hormonal therapy or systemic therapy for prostate cancer. PSMA PET findings (PROMISE miTNM stage, number of lesions) were collected from the clinical imaging reports. Descriptive statistics were used (median, range). Results: From 2002 patients screened, 146 patients were included in the analysis. Median time from primary therapy to PSMA PET was 39 (2.1-261) months. Median pre-scan PSA levels and PSA doubling time in patients who underwent RP (n=85), dRT (n=22), post-RP SRT (n=39) and overall (n=146) were 2.4 ng/mL (1-72.1), 8.3 ng/mL (2.37-202), 2.58 ng/ml (1.1-32.3), 2.7 ng/mL (1-202), and 3.5 months (1-9), 3.3 months (1-9), 4.4 months (1-9), 3.7 (1-9) months, respectively. PSMA-PET was positive in 80%, 41%, 85%, 83% of the RP, dRT, RP + SRT and overall populations, respectively. Poly-metastatic disease (≥5 lesions) was found in 19%, 32%, 21% and 21% of cases, respectively. PSMA-PET detected disease only localized to the prostate fossa (miT+N0M0) in 7%, 32%, 0% and 9% respectively. PSMA-PET detected pelvic nodal disease (miTxN1M0) in 40% 18% 28% and 34% respectively. PSMA PET detected any distant metastatic disease (miTxNxM1) in 33%, 41% 56% and 40% respectively. PSMA-PET detected metastatic nodal only disease (N1 and/or M1a) in 58% 32% 74% and 39% and osseous disease (M1b) in 19% 23% 31% and 23% cases respectively. Conclusions: In this “EMBARK-like” cohort of patients with high-risk nmCS PCa and PSA DT &lt; 9 months, PSMA PET was positive in 83% of patients, detected M1 disease in 40% of patients and over one-fifth of cases presented with 5 or more lesions. PSMA-PET provides novel additional risk stratification for patients with high-risk nmCS PCa without distant metastasis based on conventional imaging. Further studies are needed to assess its independent prognostic value and use for treatment guidance. Clinical trial information: NCT03582774 .

Prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET) disease extent and overall survival (OS) in patients (pts) with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC): An international multicenter retrospective study.

5010 Background: PSMA-PET was positive for distant metastases (39% distant nodes, 24% bone, 6% visceral organ) in &gt;50% of nmCRPC pts who were nonmetastatic by conventional imaging (Fendler et al. CCR 2019). However, the prognostic impact of PSMA-PET disease extent and its association with oncologic outcomes is unknown. We assessed the prognostic utility of PSMA-PET disease extent in nmCRPC pts defined by conventional imaging for OS and new metastases-free survival (nMFS). Methods: 200 pts (6 centers) with nmCRPC by conventional imaging and prostate-specific antigen doubling time (PSADT) ≤10 mo and/or ISUP grade group ≥4 underwent PSMA-PET. Clinical course and treatment management after PSMA-PET imaging were recorded for 4-9 y. Pt characteristics and PSMA-PET disease extent were analyzed retrospectively. OS and PSMA-PET nMFS (time from primary PSMA-PET to appearance of new distant metastases by PSMA-PET or death) were analyzed for pt subgroups based on disease extent by univariate Cox regression. Results: Median OS was 74 mo, similar to the SPARTAN study of nmCRPC pts (74 mo; Smith et al. Eur Urol 2021). Polymetastatic disease (≥5 distant lesions by PSMA-PET) was associated with shorter OS (median 61 mo vs not reached [NR]) and shorter PSMA-PET nMFS (HR 1.8, 95% CI 1.1-2.9; median 38 vs 60 mo; p=0.021). Any metastatic disease by PSMA-PET and whole-body PSMA tumor volume were not prognostic for OS and PSMA-PET nMFS (all p&gt;0.05). Initial pN1 status was associated with shorter OS (median 55 mo vs NR), but not with PSMA-PET nMFS (p&gt;0.05). Baseline age, baseline Gleason grade ≥8, prior radiotherapy (RT), and PSA and PSADT at time of primary PSMA-PET were not associated with outcomes (all p&gt;0.05). Management after PSMA-PET imaging was mostly local/targeted therapy in pts with no visible/locoregional disease (40/30%) and androgen receptor signaling inhibition therapy in pts with nodal/bone distant metastases (35/43%). Conclusions: Polymetastases (&gt;5) by PSMA-PET and initial pN1 status were significantly associated with worse OS. PSMA-PET disease extent provides a potential novel additional risk stratification for pts with nmCRPC without distant metastasis based on conventional imaging. Further validation is needed to prove its independent prognostic value. Clinical trial information: NCT01946204 . [Table: see text]

Baseline PSMA-PET/CT as a predictor of PSA persistence following radical prostatectomy in high-risk nonmetastatic prostate cancer patients receiving neoadjuvant therapy.

The precise staging and proper management of high-risk prostate cancer (PCa) continues to be a challenge. We aimed to demonstrate the prognostic value of baseline prostate-specific membrane antigen-ligand positron emission tomography/computed tomography (PSMA-PET/CT) in high-risk, nonmetastatic PCa patients who received neoadjuvant hormonal or chemohormonal treatment followed by radical prostatectomy (RP). We performed retrospective analyses of 70 patients with high-risk, nonmetastatic PCa confirmed by biopsy between 2018 and 2021. All patients underwent neoadjuvant therapy followed by RP and pelvic lymph node dissection (PLND); PSMA-PET/CT was performed before initiation of neoadjuvant therapy. Acquired image information and clinical characteristics/outcomes were examined for possible associations. Among 70 high-risk PCa patients, median age was 69 years old and median prostate specific antigen (PSA) at presentation was 58.5 ng/mL. Thirty (42.9%) patients had uptake of the PSMA tracer only in the primary PCa lesions and 40 (57.1%) patients had PSMA-positive lesions in regional or distant sites. Sixteen (32%) localized PCa patients defined by pre-PET magnetic resonance imaging were found to have locally advanced PCa based on PSMA-PET/CT. Fifteen (30%) localized PCa patients and 7 (35%) locally advanced PCa patients were upstaged to metastatic PCa. The sensitivity and specificity of PSMA-PET/CT for the detection of lymph node involvement were 90.9% and 69.5%, respectively, with a positive prediction value of 35.7% and negative prediction value of 97.6%. The diagnostic accuracy was 72.9%. Univariate analysis showed upstaging, tumor stage, and metastasis location based on PSMA-PET/CT are predictors to PSA persistence after surgery, while multivariate logistic regression analysis showed only the tumor stage based on PSMA-PET/CT remained an independent predictor of the outcome. This study further highlights the accuracy and necessity of PSMA-PET/CT in newly diagnosed, high-risk, nonmetastatic PCa patients.

Radical prostatectomy versus external beam radiotherapy with androgen deprivation therapy for high-risk prostate cancer: a systematic review

BackgroundTo summarize recent evidence in terms of health-related quality of life (HRQoL), functional and oncological outcomes following radical prostatectomy (RP) compared to external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) for high-risk prostate cancer (PCa).MethodsWe searched Medline, Embase, Cochrane Database of Systematic Reviews, Cochrane Controlled Trial Register and the International Standard Randomized Controlled Trial Number registry on 29 march 2021. Comparative studies, published since 2016, that reported on treatment with RP versus dose-escalated EBRT and ADT for high-risk non-metastatic PCa were included. The Newcastle–Ottawa Scale was used to appraise quality and risk of bias. A qualitative synthesis was performed.ResultsNineteen studies, all non-randomized, met the inclusion criteria. Risk of bias assessment indicated low (n = 14) to moderate/high (n = 5) risk of bias. Only three studies reported functional outcomes and/or HRQoL using different measurement instruments and methods. A clinically meaningful difference in HRQoL was not observed. All studies reported oncological outcomes and survival was generally good (5-year survival rates > 90%). In the majority of studies, a statistically significant difference between both treatment groups was not observed, or only differences in biochemical recurrence-free survival were reported.ConclusionsEvidence clearly demonstrating superiority in terms of oncological outcomes of either RP or EBRT combined with ADT is lacking. Studies reporting functional outcomes and HRQoL are very scarce and the magnitude of the effect of RP versus dose-escalated EBRT with ADT on HRQoL and functional outcomes remains largely unknown.

Apalutamide as a therapeutic option in case of local failure in the nmCRPC

Apalutamide is a non-steroidal selective androgen receptor inhibitor approved for the treatment of high-risk non-metastatic castration-resistant prostate cancer and metastatic hormone-sensitive prostate cancer. The paper describes a case of a patient diagnosed with prostate cancer with a long-term course of the disease. The patient was diagnosed with a non-metastatic castration-resistant stage 18 years after primary treatment. Systemic treatment with apalutamide was recommended. Initially, the treatment was carried out as part of the extended access to apalutamide program and from March 2022 as part of the B.56 drug program. The study presents the effectiveness and safety of the therapy in a 12-month follow-up period and discusses controversial aspects of the patient's previous treatments.

Darolutamide in Spanish patients with nonmetastatic castration-resistant prostate cancer: ARAMIS subgroup analysis.

Aim: Darolutamide significantly prolonged metastasis-free survival (MFS) versus placebo in the Phase III ARAMIS study. We analyzed outcomes in Spanish participants in ARAMIS. Patients & methods: Patients with high-risk nonmetastatic castration-resistant prostate cancer were randomized 2:1 to darolutamide 600 mg twice daily or placebo, plus androgen-deprivation therapy. The primary end point was MFS. Descriptive statistics are reported for this post hoc analysis. Results: In Spanish participants, darolutamide (n=75) prolonged MFS versus placebo (n=42): hazard ratio 0.345, 95% confidence interval 0.175-0.681. The incidence and type of treatment-emergent adverse events were comparable between treatment arms. Conclusion: For Spanish participants in ARAMIS, efficacy outcomes favored darolutamide versus placebo, with a similar safety profile, consistent with the overall ARAMIS population. Clinical Trials Registration: NCT02200614 (ClinicalTrials.gov).

Titration as an effective strategy to reduce apalutamide induced skin rash: A multi-institutional real-world experience.

197 Background: With increasing use of novel androgen receptor inhibitors to treat prostate cancer (PCa), better safety management has been spotlighted. Apalutamide (APA) is suggested for metastatic hormone-sensitive prostate cancer (mHSPC) and high-risk non-metastatic castrate-resistant prostate cancer (NM-CRPC). However, around 25% of patients will experience skin rash. This analysis aims to investigate whether dose titration might be effective to reduce the incidence of skin rash for apalutamide-treated patients. Methods: A retrospective analysis of 73 PCa patients received APA plus androgen deprivation therapy at 3 centers in Wenzhou, China by Aug 2022 was done. Titration was defined as starting APA from a low daily dose of 120mg or 180mg and gradually increase to 240mg. The study group was dose titration patients and compare group was patients received initial 240mg qd. 1 center used 1-week dose escalation (120mg qd in week 1, 180mg qd in week 2, 240mg qd in week 3 and after) strategy and the rest 2 centers used personalized plan (starting dose of 120 or 180mg qd, the physican decide when to increase the dose). Incidence of skin rash, Grade 3 skin rash, dose modification and termination were compared. We also compared the PSA response of two groups at 1,3 and 6 months. Results: 31 and 42 patients in study and control groups were enrolled. Median age was 75.36 years (56.0-90.0), with 1.67 m height (1.50-1.80) and 69.0 kg weight (47.5-92.0). 51% was mHSPC, 90% had Gleason score ≥ 8, 66% have a high tumor volume per CHAARTED. Incidence of skin rash was significantly lower in the study vs control (6.45% vs 26.19%, p=0.029). No patient in study vs 3 (7.5%) patients in control experienced Grade 3 rash. 2 (7.69%) and 9 (22.50%) patients in study and control had dose modification and 3 (7.5%) patients in control group terminated APA due to adverse events. PSA response was slightly lower in study group in month 1 (median PSA decline, study vs control, 85.80% vs 93.85%, p = 0.117) and was consistent in month 3 (95.17% vs 98.71, p=0.152) and month 6 (98.61% vs 99.19%, p=0.530). For selection of titration strategy, incidence of skin rash between 1-week strategy and personalized strategy was consistent (5.88% vs 7.14%, p=0.887). 1-week strategy has significantly better PSA decline at month 1 (median PSA decline, 1-week vs personalized 97.00% vs 75.54%, p=0.019) and performs slightly better in month 3 (99.29% vs 87.74%, p=0.087) vs personalized strategy, in which patients’ dose started to increase between week 2-8. Conclusions: Our results demonstrated that titration might be an effective strategy to reduce incidence of skin rash for PCa patients receiving apalutamide, with little interference to patient efficacy in PSA decline. For time frame to increase dose, 1-week plan might be a better selection. Future prospective studies are needed for validation.

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 &lt; 8 mo and/or absolute PSA &gt; 20 ng/mL and serum testosterone &lt; 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 &gt;50% PSA decline occurred in 82% with 177Lu and 71% with 111In. Grade &gt;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 &gt;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 .

Cost-effectiveness of abiraterone acetate for high-risk nnon-metastatic prostate cancer.

358 Background: In a primary analysis of the STAMPEDE protocol, the addition of Abiraterone acetate to androgen deprivation therapy (ADT) in men with castration sensitive, high-risk, non-metastatic prostate cancer was associated with significantly higher rates of metastasis-free survival compared with ADT alone. However, the cost-effectiveness of Abiraterone in this population remains unaddressed. Methods: A decision model based on partitioned survival simulations estimated costs and quality-adjusted life years (QALY), and incremental cost-effectiveness ratios (ICERs) associated with ADT with or without Abiraterone. This analysis was performed from a United States healthcare sector perspective. We estimated drug acquisition costs using the Federal Supply Schedule. Given current heterogeneity in prescription drug coverage, we used both brand-name and generic drug prices. The willingness-to-pay (WTP) threshold was $100,000 per QALY. Analyses were performed over the published STAMPEDE trial with median follow-up duration of 72 months. Model input parameters were based on the STAMPEDE trial data as well as best available and most recent data provided in the published literature. Sensitivity analyses explored uncertainty with regard to the model assumptions. Results: Using brand-name pricing, the addition of Abiraterone to ADT was associated with an increase in net costs by $217,616, and an increase in QALYS by 0.79. Therefore, the ICER associated with brand-name Abiraterone was $277,156 per QALY. Sensitivity analyses revealed that the monthly price of Abiraterone would need to be less than or equal to $2,581 in order to be cost-effective at a WTP threshold of $100,000 per QALY. In contrast, generic Abiraterone was associated with an increase in net costs by $45,325, and a cost-effective ICER of $57,726 per QALY. Conclusions: Abiraterone for high-risk non-metastatic prostate cancer is cost-effective using generic pricing. However, current brand-name pricing is roughly four times the threshold of cost-effectiveness, underscoring the need to increase access to generic drugs in the United States.

Revisiting current National Comprehensive Cancer Network (NCCN) high-risk prostate cancer stratification: a National Cancer Database analysis.

High-risk prostate cancer includes heterogenous populations with variable outcomes. This study aimed to compare the prognostic ability of individual high-risk factors, as defined by National Comprehensive Cancer Network (NCCN) risk stratification, in prostate cancer patients undergoing radical prostatectomy. We queried the National Cancer Database from 2004 to 2018 for patients with non-metastatic high-risk prostate cancer who underwent radical prostatectomy and stratified them as Group H1: Prostate specific antigen (PSA) > 20 ng/ml alone, Group H2: cT3a stage alone and Group H3: Gleason Grade (GG) group 4/5 as per NCCN guidelines. The histopathological characteristics and rate of adjuvant therapy were compared between different groups. Inverse probability weighting (IPW)-adjusted Kaplan-Meier curves were utilized to compare overall survival (OS) in group H1 and H2 with H3. Overall, 61,491 high-risk prostate cancer patients were identified, and they were classified into Group H1 (n = 14,139), Group H2 (n = 2855) and Group H3 (n = 44,497). Compared to group H1 or H2, pathological GG group > 3 (p < 0.001), pathological stage pT3b or higher (p < 0.001), lymph nodal positive disease (pN1) (p < 0.001) and rate of adjuvant therapy (p < 0.001) were significantly in Group H3. IPW-adjusted Kaplan-Meier curves showed significantly better 5-year OS in group H1 compared to group H3 [95.1% vs 93.3%, p < 0.001] and group H2 compared to group H3 [94.4% vs 92.9%, p < 0.001]. PSA > 20 ng/ml or cT3a stage in isolation have better oncologic and survival outcomes compared to GG > 3 disease and sub-stratification of 'High-risk' category might lead to better patient prognostication.

Cost-Utility Analysis of Darolutamide Combined with Androgen Deprivation Therapy for Patients with High-Risk Non-Metastatic Castration-Resistant Prostate Cancer in China.

The increasing incidence of prostate cancer (PC) in China leads to a significant disease burden. Although three novel androgen inhibitors (darolutamide, apalutamide, and enzalutamide) have been approved for patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC), the economic evaluation of these novel treatments in China remains unknown. In this study, we aimed to evaluate the cost-utility of darolutamide combined with androgen deprivation therapy (ADT), comparing with apalutamide + ADT and enzalutamide + ADT, in patients with high-risk nmCRPC from a healthcare system perspective in China. A partitioned survival model was developed to capture time spent by patients in three health states: nmCRPC, metastatic CRPC (mCRPC), and death. Clinical outcomes from the ARAMIS, PROSPER, and SPARTAN studies were obtained. In the absence of head-to-head studies, indirect treatment comparisons were conducted to capture the comparative effectiveness between darolutamide + ADT, apalutamide + ADT, and enzalutamide + ADT. The prices of apalutamide and enzalutamide were assumed to be the same as the initial launch price of darolutamide, since post-negotiation prices after national reimbursement drug list (NRDL) inclusion remain confidential. Other health resources costs, baseline characteristics, treatment patterns, and utility were collected through literature or clinical expert interviews. Selected sensitivity analyses were also performed. For a 20-year time horizon, darolutamide + ADT was associated with lower cost per quality-adjusted life years (QALYs) than apalutamide + ADT and enzalutamide + ADT (202,897 Chinese yuan (CNY)/QALY vs. 228,998CNY/QALY and 221,409CNY/QALY, respectively) (exchange rate, 1USD = 6.7871CNY). Darolutamide + ADT had better health outcomes and lower total costs compared to both apalutamide + ADT (+ 0.22QALYs and - 72,818CNY) and enzalutamide + ADT (+ 0.09QALYs and - 67,451CNY). Across the modelled sensitivity analyses (including hazard ratios and drug costs), darolutamide + ADT remained dominant or cost-effective. This economic evaluation suggested that, in comparison with apalutamide + ADT and enzalutamide + ADT, darolutamide + ADT was a dominant or cost-effective treatment option for patients with high-risk nmCRPC in China.

Management of high-risk and post-operative non-metastatic prostate cancer in Catalonia: an expert Delphi consensus.

To reach a consensus on recommendations for the management of high-risk and post-operative non-metastatic prostate cancer by a group of Radiation Oncologists in Catalonia dedicated to prostate cancer. A modified Delphi approach was employed to reach consensus on controversial topics in Radiation Oncology on high-risk non-metastatic (eight questions) and post-operative (eight questions) prostate cancer. An agreement of at least 75% was considered as consensus. The survey was electronically sent 6weeks before an expert meeting where topics were reviewed and discussed. A second-round survey for the controversial questions only was sent and answered by participants after the meeting. After the first round of the survey, 19 experienced Radiation Oncologists attended the meeting and 74% fulfilled the second-round online questionnaire. An agreement of 9 of the 16 questions was accounted for the first round. After the meeting, an additional agreement was reached in 3 questions leading to a final consensus on 12 of the 16 questions. There are still controversial topics like the use of PET for staging of high-risk and post-operative non-metastatic prostate cancer and the optimal dose to the prostate bed in the salvage setting. This consensus contributes to establish recommendations and a framework to help in prostate cancer radiation therapy and pharmacological management in daily clinical practice of high-risk and post-operative non-metastatic prostate cancer.