Natural History of Nonmetastatic Prostate Cancer Managed With Watchful Waiting.

Importance: It is uncertain to what extent watchful waiting (WW) in men with nonmetastatic prostate cancer (PCa) and a life expectancy of less than 10 years is associated with adverse consequences. Objective: To report transitions to androgen deprivation therapy (ADT), castration-resistant prostate cancer (CRPC), death from PCa, or death from other causes in men treated with a WW strategy. Design, Setting, and Participants: This nationwide, population-based cohort study included men with nonmetastatic PCa diagnosed since 2007 and registered in the National Prostate Cancer Register of Sweden with WW as the primary treatment strategy and with life expectancy less than 10 years. Life expectancy was calculated based on age, the Charlson Comorbidity Index (CCI), and a drug comorbidity index. Observed state transition models complemented observed data to extend follow-up to more than 20 years. Analyses were performed between 2022 and 2023. Exposure: Nonmetastatic PCa. Main Outcomes and Measures: Transitions to ADT, CRPC, death from PCa, and death from other causes were measured using state transition modeling. Results: The sample included 5234 men (median [IQR] age at diagnosis, 81 [79-84] years). After 5 years, 954 men with low-risk PCa (66.2%) and 740 with high-risk PCa (36.1%) were still alive and not receiving ADT. At 10 years, the corresponding proportions were 25.5% (n = 367) and 10.4% (n = 213), respectively. After 10 years, 59 men with low-risk PCa (4.1%) and 221 with high-risk PCa (10.8%) had transitioned to CRPC. Ten years after diagnosis, 1330 deaths in the low-risk group (92.3%) and 1724 in the high-risk group (84.1%) were from causes other than PCa. Conclusions and Relevance: These findings suggest that the WW management strategy is appropriate for minimizing adverse consequences of PCa in men with a baseline life expectancy of less than 10 years.

Efficacy of Combination Therapy With Radium-223 and Enzalutamide in Castration-resistant Prostate Cancer With Bone Metastases.

BACKGROUND/AIM: Radium-223 therapy has been reported to improve prognosis in patients with castration-resistant prostate cancer (CRPC) and bone metastases. Occasionally, radium-223 and androgen receptor signaling inhibitors (ARSIs) are used in combination for disease control, but the efficacy of this combination is unclear. This study assessed the efficacy of the addition of enzalutamide in patients treated with radium-223. PATIENTS AND METHODS: We included patients with CRPC and bone metastases who were treated with radium-223 at our institution. Patients were assigned to the enzalutamide combination group or non-combination group. We compared progression-free survival (PFS), overall survival (OS), and the completion rate of radium-223 between the two groups. RESULTS: In total, 39 patients with CRPC were included in this retrospective study. The median follow-up duration was 8.8 months. The enzalutamide combination and non-combination groups included 22 (56.4%) and 17 patients (43.6%), respectively. Median PFS was 11.3 months [95% confidence interval (CI)=3.9-19.9] in the combination group, versus 3.0 months (95%CI=1.9-5.5) in the non-combination group (p=0.004). Median OS did not significantly differ between the groups. The radium-223 completion rate was higher in the combination group than in the non-combination group (72.7% vs. 35.3%, p=0.026). CONCLUSION: The combined use of enzalutamide with radium-223 therapy improved PFS and treatment completion rates in patients with CRPC and bone metastases. This combination may be associated with a more favorable prognosis.

Natural course of metastatic castration-resistant prostate cancer in the era of intensified androgen deprivation therapy in the hormone-sensitive setting.

BACKGROUND: Androgen deprivation therapy (ADT) intensification (ADTi) (i.e., ADT with androgen receptor pathway inhibitor or docetaxel, or both) has significantly improved survival outcomes of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, the impact of prior ADTi in the mHSPC setting on the disease presentation and survival outcomes in metastatic castration-resistant prostate cancer (mCRPC) is not well characterized. In this study, our objective was to compare the disease characteristics and survival outcomes of patients with new mCRPC with respect to receipt of intensified or nonintensified ADT in the mHSPC setting. METHODS: In this institutional review board-approved retrospective study, eligibility criteria were as follows: patients diagnosed with mCRPC, treated with an approved first-line mCRPC therapy, and who received either intensified or nonintensified ADT in the mHSPC setting. Progression-free survival (PFS) was defined from the start of first-line therapy for mCRPC to progression per Prostate Cancer Working Group 2 criteria or death, and overall survival (OS) was defined from the start of first-line therapy for mCRPC to death or censored at the last follow-up. A multivariable analysis using the Cox proportional hazards model was used, adjusting for potential confounders. RESULTS: Patients (n = 387) treated between March 20, 2008, and August 18, 2022, were eligible and included: 283 received nonintensified ADT, whereas 104 were treated with ADTi. At mCRPC diagnosis, patients in the ADTi group were significantly younger, had more visceral metastasis, lower baseline prostate-specific antigen (all p < 0.01), and lower hemoglobin (p = 0.027). Furthermore, they had significantly shorter PFS (median 4.8 vs. 8.4 months, adjusted hazard ratio [HR]: 1.46, 95% confidence interval [95% CI]: 1.07-2, p = 0.017) and OS (median 21.3 vs. 33.1 months, adjusted HR: 1.53, 95% CI: 1.06-2.21, p = 0.022) compared to patients in the nonintensified ADT group. CONCLUSION: Patients treated with ADTi in the mHSPC setting and experiencing disease progression to mCRPC had more aggressive disease features of mCRPC (characterized by a higher number of poor prognostic factors at mCRPC presentation). They also had shorter PFS on first-line mCRPC treatment and shorter OS after the onset of mCRPC compared to those not receiving ADTi in the mHSPC setting. Upon external validation, these findings may impact patient counseling, prognostication, treatment selection, and design of future clinical trials in the mCRPC setting. There remains an unmet need to develop novel life-prolonging therapies with new mechanisms of action to improve mCRPC prognosis in the current era.

[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. METHODS: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. FINDINGS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. INTERPRETATION: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. FUNDING: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Radiographic Progression at Castration-Resistant Prostate Cancer Diagnosis: A Prognostic Indicator of Metastatic Hormone-Sensitive Prostate Cancer.

BACKGROUND: The critical role of radiographic assessment at the time of castration-resistant prostate cancer (CRPC) diagnosis is underscored by this study. We performed a retrospective analysis of radiographic changes in metastasis from the time of diagnosis of metastatic hormone-sensitive prostate cancer (mHSPC) to CRPC diagnosis. We also explored its impact on prognosis post-CRPC. MATERIALS AND METHODS: We retrospectively analyzed 98 men who underwent radiographic examinations (bone scans and computed tomography [CT]) at the time of CRPC diagnosis. When radiographic studies demonstrated progression at CRPC diagnosis, patients were assigned to the radiographic progressive disease (rPD) group. The remaining patients were placed in the "non-rPD" group. The overall survival (OS) post-CRPC was compared between the 2 groups. RESULTS: The median OS post-CRPC was significantly shorter in the rPD group (n = 50) compared to the non-rPD group (n = 48) (32 months vs. not reached, P = .0124). Multivariate analysis showed that radiographic progression and shorter time to CRPC were associated with a shorter OS post-CRPC (hazard ratio [HR] = 3.14; 95% confidence interval [CI], 1.21-8.12, P = .019). CONCLUSION: Radiographic progression at the point of CRPC diagnosis independently predicts a shorter OS post-CRPC in patients with mHSPC. Therefore, assessing radiographic changes at the time of CRPC diagnosis could be instrumental in managing CRPC in patients with mHSPC.

Clinical validation of circulating GDF15/MIC-1 as a marker of response to docetaxel and survival in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Elevated circulating growth differentiation factor (GDF15/MIC-1), interleukin 4 (IL4), and IL6 levels were associated with resistance to docetaxel in an exploratory cohort of men with metastatic castration-resistant prostate cancer (mCRPC). This study aimed to establish level 2 evidence of cytokine biomarker utility in mCRPC. METHODS: IntVal: Plasma samples at baseline (BL) and Day 21 docetaxel (n = 120). ExtVal: Serum samples at BL and Day 42 of docetaxel (n = 430). IL4, IL6, and GDF15 levels were measured by ELISA. Monocytes and dendritic cells were treated with 10% plasma from men with high or low GDF15 or recombinant GDF15. RESULTS: IntVal: Higher GDF15 levels at BL and Day 21 were associated with shorter overall survival (OS) (BL; p = 0.03 and Day 21; p = 0.004). IL4 and IL6 were not associated with outcomes. ExtVal: Higher GDF15 levels at BL and Day 42 predicted shorter OS (BL; p < 0.0001 and Day 42; p < 0.0001). Plasma from men with high GDF15 caused an increase in CD86 expression on monocytes (p = 0.03), but was not replicated by recombinant GDF15. CONCLUSIONS: Elevated circulating GDF15 is associated with poor prognosis in men with mCRPC receiving docetaxel and may be a marker of changes in the innate immune system in response to docetaxel resistance. These findings provide a strong rationale to consider GDF15 as a biomarker to guide a therapeutic trial of drugs targeting the innate immune system in combination with docetaxel in mCRPC.

Prostate-specific Membrane Antigen Positron Emission Tomography-detected Disease Extent and Overall Survival of Patients with High-risk Nonmetastatic Castration-resistant Prostate Cancer: An International Multicenter Retrospective Study.

Previously, we demonstrated that prostate-specific membrane antigen positron emission tomography (PSMA-PET) revealed distant metastases in 109/200 patients (39% distant nodes, 24% bone, and 6% visceral organ) with nonmetastatic castration-resistant prostate cancer (nmCRPC) and high-risk features (International Society of Urological Pathology score ≥4 and/or prostate-specific antigen doubling time ≤10 mo) without metastases by conventional imaging. However, the impact of disease extent determined by PSMA-PET on patient outcomes is unknown. We followed these 200 patients for a median of 43 mo after PSMA-PET and retrospectively assessed the association between patient characteristics, PSMA-PET findings, treatment management, and outcomes using a Kaplan-Meier model and Cox multivariable regressions. Among assessed disease characteristics, polymetastatic disease (five or more distant lesions on PET) was independently associated with shorter overall survival (OS; median 61 mo vs not reached; hazard ratio [95% confidence interval], 1.81 [1.00-3.27]; p = 0.050) and time to new metastases (median 38 vs 60 mo; 1.80 [1.10-2.96]; p = 0.019), and initial pN1 status with shorter OS (55 mo vs not reached; 1.94 [1.12-3.37]; p = 0.019). Following PSMA-PET, locoregional salvage therapies were used most commonly in no/local disease (58%), and androgen receptor signaling inhibitors were used in distant metastatic disease (51%). PSMA-PET provides additional risk stratification for patients with nmCRPC. Polymetastatic disease (five or more distant lesions) is associated with worse outcomes. PATIENT SUMMARY: A novel sensitive imaging technology, called prostate-specific membrane antigen positron emission tomography (PSMA-PET), allows doctors to detect the spread of prostate cancer, known as distant metastases, earlier and more accurately than in the past. In our study, PSMA-PET detected none to many metastases in patients who were considered free of distant metastasis by conventional imaging. These findings predicted outcomes and were used to select appropriate treatment.

Treatment patterns and outcomes in metastatic castration-resistant prostate cancer patients with and without somatic or germline alterations in homologous recombination repair genes.

BACKGROUND: Although germline BRCA mutations have been associated with adverse outcomes in prostate cancer (PC), understanding of the association between somatic/germline alterations in homologous recombination repair (HRR) genes and treatment outcomes in metastatic castration-resistant PC (mCRPC) is limited. The aim of this study was to investigate the prevalence and outcomes associated with somatic/germline HRR alterations, particularly BRCA1/2, in patients initiating first-line (1L) mCRPC treatment with androgen receptor signalling inhibitors (ARSi) or taxanes. PATIENTS AND METHODS: Data from 729 mCRPC patients were pooled for CAPTURE from four multicentre observational studies. Eligibility required 1L treatment with ARSi or taxanes, adequate tumour samples and biomarker panel results. Patients underwent paired normal and tumour DNA analyses by next-generation sequencing using a custom gene panel including ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2, RAD51B and RAD54L. Patients were divided into subgroups based on somatic/germline alteration(s): with BRCA1/2 mutations (BRCA); with HRR mutations except BRCA1/2 (HRR non-BRCA); and without HRR alterations (non-HRR). Patients without BRCA1/2 mutations were classified as non-BRCA. Radiographic progression-free survival (rPFS), progression-free survival 2 (PFS2) and overall survival (OS) were assessed. RESULTS: Of 729 patients, 96 (13.2%), 127 (17.4%) and 506 (69.4%) were in the BRCA, HRR non-BRCA and non-HRR subgroups, respectively. BRCA patients performed significantly worse for all outcomes than non-HRR or non-BRCA patients (P < 0.05), while PFS2 and OS were significantly shorter for BRCA than HRR non-BRCA patients (P < 0.05). HRR non-BRCA patients also had significantly worse rPFS, PFS2 and OS than non-HRR patients. Exploratory analyses suggested that for BRCA patients, there were no significant differences in outcomes associated with 1L treatment choice (ARSi or taxanes) or with the somatic/germline origin of the alterations. CONCLUSIONS: Worse outcomes were observed for mCRPC patients in the BRCA subgroup compared with non-BRCA subgroups, either HRR non-BRCA or non-HRR. Despite its heterogeneity, the HRR non-BRCA subgroup presented worse outcomes than the non-HRR subgroup. Screening early for HRR mutations, especially BRCA1/2, is crucial in improving mCRPC patient prognosis.

Risk Factors for Early Treatment Discontinuation Due to Toxicity Among Patients With Metastatic Castration-resistant Prostate Cancer Receiving Androgen Receptor-targeted Therapy.

OBJECTIVES: Androgen receptor-targeted therapies (ARTs) improve survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC); however, a significant portion of patients discontinue treatment for various reasons including treatment-related toxicity. We aim to describe reasons for ART treatment discontinuation and identify predictors associated with increased risk of treatment discontinuation due to toxicity. METHODS: We performed a single-institution retrospective review of patients with mCRPC receiving ART between 2010 and 2021. Our primary aim was to identify risk factors for treatment discontinuation due to toxicity. Our secondary aim was to describe ART discontinuation patterns among patients with mCRPC. RESULTS: One hundred thirty-three patients with mCRPC started and discontinued ARTs. Fourteen patients (10.5%) discontinued treatment due to toxicity. Common reasons for treatment discontinuation include Prostate Specific Antigen test progression, radiographic progression, toxicity, and death. Significant predictors of treatment discontinuation due to toxicity on bivariate analysis and multivariate analysis included patient-reported falls (odds ratio [OR]: 7.67, CI: [1.31-40.42]; P =0.016), rash (OR: 13.4, CI: [1.35-134.81]; P =0.026), and weakness (OR: 4.16, CI: [1.15-15.0]; P =0.019). CONCLUSIONS: Our work presents the first description of ART treatment discontinuation and its causes in the real-world setting, as well as patient-reported side effects. Most patients with mCRPC discontinued treatment due to the progression of disease and a minority of patients discontinued secondary to treatment toxicity. Initial multivariable analysis suggests that patient-reported weakness, falls, and rash were associated with a higher likelihood of treatment discontinuation due to toxicity. Early monitoring of this population can prolong the duration of treatment and prevent unnecessary treatment burden.

Survival Outcomes by Race and Ethnicity in Veterans With Nonmetastatic Castration-Resistant Prostate Cancer.

Importance: Racial and ethnic disparities in prostate cancer are poorly understood. A given disparity-related factor may affect outcomes differently at each point along the highly variable trajectory of the disease. Objective: To examine clinical outcomes by race and ethnicity in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) within the US Veterans Health Administration. Design, Setting, and Participants: A retrospective, observational cohort study using electronic health care records (January 1, 2006, to December 31, 2021) in a nationwide equal-access health care system was conducted. Mean (SD) follow-up time was 4.3 (3.3) years. Patients included in the analysis were diagnosed with prostate cancer from January 1, 2006, to December 30, 2020, that progressed to nmCRPC defined by (1) increasing prostate-specific antigen levels, (2) ongoing androgen deprivation, and (3) no evidence of metastatic disease. Patients with metastatic disease or death within the landmark period (3 months after the first nmCRPC evidence) were excluded. Main Outcomes and Measures: The primary outcome was time from the landmark period to death or metastasis; the secondary outcome was overall survival. A multivariate Cox proportional hazards model, Kaplan-Meier estimates, and adjusted survival curves were used to evaluate outcome differences by race and ethnicity. Results: Of 12 992 patients in the cohort, 826 patients identified as Hispanic (6%), 3671 as non-Hispanic Black (28%; henceforth Black), 7323 as non-Hispanic White (56%; henceforth White), and 1172 of other race and ethnicity (9%; henceforth other, including American Indian or Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, unknown by patient, and patient declined to answer). Median time elapsed from nmCRPC to metastasis or death was 5.96 (95% CI, 5.58-6.34) years for Black patients, 5.62 (95% CI, 5.11-6.67) years for Hispanic patients, 4.11 (95% CI, 3.96-4.25) years for White patients, and 3.59 (95% CI, 3.23-3.97) years for other patients. Median unadjusted overall survival was 6.26 (95% CI, 6.03-6.46) years among all patients, 8.36 (95% CI, 8.0-8.8) years for Black patients, 8.56 (95% CI, 7.3-9.7) years for Hispanic patients, 5.48 (95% CI, 5.2-5.7) years for White patients, and 4.48 (95% CI, 4.1-5.0) years for other patients. Conclusions and Relevance: The findings of this cohort study of patients with nmCRPC suggest that differences in outcomes by race and ethnicity exist; in addition, Black and Hispanic men may have considerably improved outcomes when treated in an equal-access setting.

Circulating Tumor DNA Biomarkers for Response Assessment in Prostate Cancer.

Circulating tumor DNA (ctDNA) is measurable in the majority of metastatic castration-resistant prostate cancer patients. Data indicate that ctDNA present at baseline can serve as a prognostic biomarker and changes in the ctDNA posttreatment can rapidly predict both time to progression and survival. See related article by Tolmeijer et al., p. 2835.

Efficacy of New Therapies for Relapse After Docetaxel Treatment of Bone Metastatic Castration-resistant Prostate Cancer in Clinical Practice.

BACKGROUND/AIM: To assess the efficacy of novel therapeutic agents, such as androgen receptor axis-targeted agents (ARATs) and cabazitaxel, for relapse of metastatic castration-resistant prostate cancer (mCRPC) after docetaxel in real-world practice, we performed a subanalysis using database from PROSTAT-BSI, a prospective observational study to evaluate the utility of software for quantifying bone metastases on bone scintigraphy. PATIENTS AND METHODS: Patients with clinically relapsed mCRPC after docetaxel treatment who received the new agents (NEW group) and those who did not (standard of care, SOC group) were included; patients who received ARAT before DOC treatment were excluded. Overall survival (OS) after docetaxel treatment was compared between the NEW and SOC groups. RESULTS: Patients in the NEW group had significantly better OS from the start of docetaxel than those in the SOC group (the median OS in NEW and SOC was 28.9 months vs. 14.5 months, respectively). Furthermore, regardless of the time from androgen-deprivation therapy to the start of docetaxel at mCRPC, the NEW group had a better OS from relapse after docetaxel than the SOC group. CONCLUSION: In clinical practice, OS of patients with relapse after docetaxel was significantly improved in the NEW group over the SOC group.

Expression of Fibroblast Activation Protein Is Enriched in Neuroendocrine Prostate Cancer and Predicts Worse Survival.

BACKGROUND: Advanced prostate cancer (PC) may accumulate genomic alterations that hallmark lineage plasticity and transdifferentiation to a neuroendocrine (NE) phenotype. Fibroblast activation protein (FAP) is a key player in epithelial-to-mesenchymal transition (EMT). However, its clinical value and role in NE differentiation in advanced PC has not been fully investigated. METHODS: Two hundred and eight patients from a multicenter, prospective cohort of patients with metastatic castration-resistant prostate cancer (CRPC) with available RNA sequencing data were analyzed for tumor FAP mRNA expression, and its association with overall survival (OS) and NE tumor features was investigated. RESULTS: Twenty-one patients (10%) were found to have high FAP mRNA expression. Compared to the rest, this subset had a proportionally higher exposure to taxanes and AR signaling inhibitors (abiraterone or enzalutamide) and was characterized by active NE signaling, evidenced by high NEPC- and low AR-gene expression scores. These patients with high tumor mRNA FAP expression had a more aggressive clinical course and significantly shorter survival (12 months) compared to those without altered FAP expression (28 months, log-rank p = 0.016). CONCLUSIONS: FAP expression may serve as a valuable NE marker indicating a worse prognosis in patients with metastatic CRPC.

Outcomes Among African American and Non-Hispanic White Men With Metastatic Castration-Resistant Prostate Cancer With First-Line Abiraterone.

Importance: Prospective evidence suggests abiraterone is associated with superior progression-free survival for African American men compared with non-Hispanic White men with metastatic castration-resistant prostate cancer (mCRPC). Objective: To investigate differences in outcomes with first-line abiraterone therapy between African American and non-Hispanic White men with mCRPC in a national real-world cohort. Design, Setting, and Participants: This retrospective cohort study used a nationwide electronic health record-derived database of 3808 men receiving first-line therapy for mCRPC between January 1, 2012, and December 31, 2018. Data analysis was performed between January 1, 2020, and June 1, 2021. Median follow-up was 13 months (IQR, 7-22 months). Propensity score-based inverse probability of treatment weighting was applied to reduce imbalance in measured confounders between patients receiving first-line abiraterone vs other first-line therapies. Deidentified patient data originated from a geographically diverse set of approximately 280 cancer clinics (approximately 800 sites of care) throughout the United States. Participants had newly diagnosed mCRPC and were receiving first-line systemic therapy during the study period. Exposures: Receipt of abiraterone for first-line therapy. Main Outcomes and Measures: Overall survival from start of first-line treatment. Stratified analyses investigated overall survival within each race group, with first-line enzalutamide as the comparator. Results: Among 3808 patients with mCRPC, there were 2615 non-Hispanic White men (68.7%; mean [SD] age at diagnosis, 74 [8] years) and 404 African American men (10.6%; mean [SD] age at diagnosis, 69 [9] years), and 1729 patients (45.4%) in the cohort received first-line abiraterone. Among patients receiving first-line abiraterone, African American men had higher median overall survival than non-Hispanic White men (23 months [IQR, 10-37 months] vs 17 months [IQR, 9-32 months], respectively; inverse probability of treatment weighting hazard ratio, 0.76; 95% CI, 0.60-0.98). A race-by-treatment interaction existed for first-line abiraterone vs first-line enzalutamide (hazard ratio for abiraterone vs enzalutamide: non-Hispanic White men, 1.21 [95% CI, 1.06-1.38]; African American men, 1.05 [95% CI, 0.74-1.50]; interaction P = .02). There was no overall survival difference between first-line abiraterone and first-line enzalutamide among African American patients (24 vs 24 months, respectively; inverse probability of treatment weighting hazard ratio, 1.05; 95% CI, 0.74-1.50). First-line abiraterone was associated with decreased median overall survival relative to first-line enzalutamide among non-Hispanic White patients (17 months [IQR, 9-32 months] vs 20 months [IQR, 10-36 months], respectively; inverse probability of treatment weighting hazard ratio, 1.21; 95% CI, 1.06-1.38). Conclusions and Relevance: In this cohort study of patients who received first-line systemic therapy for mCRPC, African American men who received abiraterone had improved overall survival compared with non-Hispanic White men. Future prospective studies should assess drivers of differential abiraterone outcomes in mCRPC between African American and non-Hispanic White men, including differences in genetic factors and socioeconomic status, to inform treatment strategies.

Ra-223 and Ethinylestradiol Combination Therapy in Castration-resistant Prostate Cancer.

BACKGROUND/AIM: Ra-223 is a therapeutic agent for bone metastatic castration-resistant prostate cancer (mCRPC). We examined the efficacy of a treatment method using Ra-223 together with ethinylestradiol (EE). PATIENTS AND METHODS: Patients who received Ra-223 three or more times were included and two groups (with or without EE) were compared retrospectively. RESULTS: Eighteen patients were treated with Ra-223 and EE concomitantly (EstRadium therapy) and 13 patients were treated with Ra-223 alone or Ra-223 and agents other than EE (non-EstRadium therapy). The number of patients with decreased serum prostate-specific antigen level was significantly higher in the EstRadium therapy group than in the non-EstRadium therapy group (p=0.029). CONCLUSION: The combination of Ra-223 and EE, compared to Ra-223 alone, is an effective treatment option for bone mCRPC patients, in terms of PSA response.

Urinary microRNAs can predict response to abiraterone acetate in castration resistant prostate cancer: A pilot study.

BACKGROUND: Despite novel agents have been introduced to treat castration resistant prostate cancer (CRPC) during the last decade, up to one-third of CRPC patients face primary resistance to new generation compounds. Therefore, sensitive molecular tools are urgently needed for reliable treatment selection and response prediction. This study aimed to evaluate urinary miRNAs and blood circulating androgen receptor (AR) transcript level as a tool for noninvasive outcome prediction for CRPC patients undergoing abiraterone acetate (AA) therapy. METHODS: Prostate cancer-specific miR-148a, -365, -375, and -429 were analyzed in 129 urine samples collected from 100 CRPC patients before and during AA therapy via quantitative reverse transcription PCR. To test the prognostic value, urinary miRNA levels alone, as well as combined with AR level were associated with progression-free survival (PFS) and overall survival (OS). RESULTS: Level of urinary miR-375 was the highest in CRPC in comparison to noncancerous controls, as well as in combination with miR-429 was predictive for short PFS in AA-treated patients (HR = 2.2, 95% CI: 1.1-4.2, p = 0.023). Especially high prognostic power of all analyzed miRNAs was observed in CRPC cases with high blood AR levels. For PFS prediction a tandem of miR-429 and high AR reached HR of 5.0 (95% CI: 2.2-11.8, p < 0.001), while for prediction of OS the best combination was demonstrated by miR-148a and AR with HR of 3.1 (95% CI: 1.4-7.1, p = 0.006). CONCLUSIONS: Urinary miRNAs could be used as prognostic biomarkers for CRPC patients to predict response to AA therapy, especially for the cases with high blood AR levels.

Real-world outcomes of second novel hormonal therapy or radium-223 following first novel hormonal therapy for mCRPC.

Aim: To evaluate real-world clinical outcomes of radium-223 or alternative novel hormonal therapy (NHT) following first-line NHT for metastatic castration-resistant prostate cancer (mCRPC). Patients & methods: Retrospective analysis of the US Flatiron database (ClinicalTrials.gov identifier: NCT03896984). Results: In the radium-223 cohort (n = 120) versus the alternative NHT cohort (n = 226), proportionally more patients had prior symptomatic skeletal events and bone-only metastases, and first-line NHT duration was shorter. Following second-line therapy, 49 versus 39% of patients received subsequent life-prolonging therapy; of these, 47 versus 76% received taxane. Median overall survival was 10.8 versus 11.2 months. Conclusion: Real-world patients with mCRPC had similar median overall survival following second-line radium-223 or alternative NHT after first-line NHT. Many patients received subsequent therapy, with less taxane use after radium-223.

Lay abstract Patients with metastatic castration-resistant prostate cancer are often first treated with novel hormonal therapy (NHT) using abiraterone or enzalutamide. To aid decisions about what treatment to use next, we reviewed information about patients who were treated with an alternative NHT (226 patients) or the nuclear medicine radium-223 (120 patients) after the first NHT. Most patients given radium-223 had cancer that had spread to their bones only, whereas many patients given an alternative NHT had cancer in their bones and other parts of their body. Around one in four patients given radium-223 and one in five given an alternative NHT had symptoms related to their bone metastases after starting treatment. Five in every ten patients given radium-223 received further therapy, including chemotherapy in 50% of these patients, while four in every ten patients given an alternative NHT received further therapy, including chemotherapy in 75%. On average, patients lived for almost a year after starting radium-223 or an alternative NHT.

A meta-analysis on overall survival and safety outcomes in patients with nonmetastatic castration-resistant prostate cancer treated with novel hormonal agents.

Several novel androgen receptor (AR)-inhibitors have been introduced for nonmetastatic castration-resistant prostate cancer (nmCRPC) treatment, with the improvement of survival outcomes which need to be balanced against the risk of adverse events. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating enzalutamide, apalutamide and darolutamide in nmCRPC patients, to assess overall survival (OS), incidence and risk of adverse drug events, adverse-events-related death and adverse-events-related treatment discontinuation. We selected three RCTs (SPARTAN, PROSPER and ARAMIS). New hormonal agents administration resulted in better OS, despite the increased risk of several any grade and grade 3-4 adverse events. In the decision-making process, careful evaluation of expected adverse events, patients' comorbidities and maintenance of quality of life are mandatory.

Clinical characteristics and outcomes for patients with non­metastatic castration-resistant prostate cancer.

This study used linked, routinely-collected datasets to explore incidence, clinical characteristics and outcomes of prostate cancer (PC) patients who experience a rise in prostate-specific antigen (PSA) levels despite androgen deprivation therapy (ADT), without evidence of metastases in their patient record, termed non-metastatic castration-resistant PC (nmCRPC). Routinely collected administrative data in Wales were used to identify patients diagnosed with PC and nmCRPC from 2000-2015. Logrank tests and Cox proportional hazard models were used to compare time-to-events across subgroups defined by PSA doubling time and age. Of 38,021 patients identified with PC, 1,465 met nmCRPC criteria. PC incidence increased over the study period, while nmCRPC categorizations reduced. Median time from PC diagnosis to nmCRPC categorization was 3.07 years (95% confidence interval [CI] 2.91-3.26) and from nmCRPC categorization to metastases/death was 2.86 years (95% CI 2.67-3.09). Shorter PSA doubling time (≤ 10 months, versus > 10 months) was associated with reduced time to metastases or death (2.11 years [95% CI 1.92-2.30] versus 5.22 years [95% CI 4.87-5.51]). Age was not significantly associated with time to metastases/death. Our findings highlight key clinical characteristics and outcomes for patients with nmCRPC prior to the introduction of recently approved treatments.