Expert Perspectives on Controversies in Metastatic Castration-Resistant Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 2.

Background: Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature. Materials and Methods: The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators. Results: This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1/2 mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)-positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non-BRCA1/2 mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies. Conclusions: The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.

Expert Perspectives on Controversies in Castration-Sensitive Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 1.

Purpose: Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC. Materials and Methods: The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy. Results: The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC. Conclusions: CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.

Metastatic Hormone-Sensitive Prostate Cancer and Combination Treatment Outcomes: A Review.

Importance: Metastatic hormone-sensitive prostate cancer is currently an incurable disease. Despite a high response rate to androgen-deprivation therapy, most cases progress to castration-resistant disease, the terminal phase. This review provides a summary of the most recent evidence for current and emerging management strategies, including treatment intensification with combinations of therapies. It also provides recommendations on applying the evidence in clinical practice to encourage appropriate treatment to improve survival outcomes among patients with metastatic hormone-sensitive prostate cancer. Observations: Androgen-deprivation therapy is the backbone of treatment for metastatic hormone-sensitive prostate cancer; however, it is insufficient alone to provide sustained disease control and long-term survival. Addition of an androgen receptor pathway inhibitor and/or docetaxel significantly improves survival, as demonstrated by several international phase 3 randomized clinical trials. Triplet therapy composed of androgen-deprivation therapy plus an androgen receptor pathway inhibitor plus docetaxel has been shown to improve overall survival over androgen-deprivation therapy plus docetaxel. In the ARASENS trial (darolutamide), the hazard ratios (HRs) were 0.68 (95% CI, 0.57-0.80) in the overall population; 0.71 (95% CI, 0.59-0.85) and 0.61 (95% CI, 0.35-1.05) in patients with de novo and recurrent disease, respectively; 0.69 (95% CI, 0.57-0.82) and 0.72 (95% CI, 0.41-1.13) in patients with high-volume and low-volume disease, respectively; and 0.71 (95% CI, 0.58-0.86) and 0.62 (95% CI, 0.42-0.90) in patients with high-risk and low-risk disease, respectively. In the PEACE-1 trial (abiraterone acetate + prednisone), the HRs were 0.75 (95% CI, 0.59-0.95; all de novo) in the overall population and 0.72 (95% CI, 0.55-0.95) and immature in the high-volume and low-volume subgroups, respectively. In the ENZAMET trial (enzalutamide), the HRs were 0.82 (95% CI, 0.63-1.06) in the overall population; 0.73 (95% CI, 0.55-0.99) and 1.10 (95% CI, 0.65-1.86) in the de novo and recurrent subgroups, respectively; and 0.87 (95% CI, 0.66-1.17) and 0.61 (95% CI, 0.33-1.10) in the high-volume and low-volume subgroups. Combination regimens are generally well tolerated, with adverse effects dependent on the profiles of the component drugs. Conclusions and relevance: The findings of this review show compelling evidence from phase 3 randomized clinical trials in favor of initiating triplet combination therapy for patients with metastatic hormone-sensitive prostate cancer for the best overall survival. Patients who are eligible for chemotherapy should be offered androgen-deprivation therapy plus an androgen receptor pathway inhibitor plus docetaxel, particularly patients with high-volume, high-risk, or de novo metastatic disease.

Deep and Durable Prostate-specific Antigen Response to Darolutamide with Androgen Deprivation Therapy and Docetaxel, and Association with Clinical Outcomes for Patients with High- or Low-volume Metastatic Hormone-sensitive Prostate Cancer: Analyses of the Randomized Phase 3 ARASENS Study.

BACKGROUND AND OBJECTIVE: Addition of darolutamide to androgen deprivation therapy (ADT) and docetaxel significantly improved overall survival (OS) in ARASENS (NCT02799602). Here we report on prostate-specific antigen (PSA) responses and their association with outcomes. METHODS: ARASENS is an international, double-blind, phase 3 study in patients with metastatic hormone-sensitive prostate cancer (mHSPC) randomized to darolutamide 600 mg orally twice daily (n = 651) or placebo (n = 654), both with ADT + docetaxel. The proportion of patients with undetectable PSA (<0.2 ng/ml) and time to PSA progression (≥25% relative and ≥2 ng/ml absolute increase from nadir) were compared between groups in prespecified exploratory analyses. PSA outcomes by disease volume and the association of undetectable PSA with OS and times to castration-resistant prostate cancer (CRPC) and PSA progression were assessed in post hoc analyses. KEY FINDINGS AND LIMITATIONS: The proportion of patients with undetectable PSA at any time was more than doubled with darolutamide versus placebo, at 67% versus 29% in the overall population, 62% versus 26% in the high-volume subgroup, and 84% versus 38% in the low-volume subgroup. Darolutamide delayed time to PSA progression versus placebo, with hazard ratios of 0.26 (95% confidence interval [CI] 0.21-0.31) in the overall population, 0.30 (95% CI 0.24-0.37) in the high-volume subgroup, and 0.093 (95% CI 0.047-0.18) in the low-volume subgroup. Undetectable PSA at 24 wk was associated with longer OS, with a hazard ratio of 0.49 (95% CI 0.37-0.65) in the darolutamide group, as well as longer times to CRPC and PSA progression, with similar findings in the disease volume subgroups. CONCLUSIONS AND CLINICAL IMPLICATIONS: Darolutamide + ADT + docetaxel led to deep and durable PSA responses in patients with high- or low-volume mHSPC. Achievement of undetectable PSA (<0.2 ng/ml) was correlated with better clinical outcomes. PATIENT SUMMARY: For patients with metastatic hormone-sensitive prostate cancer being treated with androgen deprivation therapy and docetaxel, PSA (prostate-specific antigen) became undetectable (below 0.2 ng/ml) in 67% of those also receiving darolutamide versus 29% of patients also receiving placebo. On average, patients achieving undetectable PSA lived longer than patients with detectable PSA.

Three- and Seven-month Prostate-specific Antigen Levels as Prognostic Markers for Overall Survival in Metastatic Hormone-sensitive Prostate Cancer: Results from SWOG S1216, a Phase 3 Randomized Trial of Androgen Deprivation Plus Orteronel or Bicalutamide.

BACKGROUND: A robust decrease in prostate-specific antigen (PSA) in response to androgen deprivation therapy (ADT) has been evaluated as a prognostic factor in patients with metastatic hormone-sensitive prostate cancer (mHSPC) since 2006, but the treatment of mHSPC has since evolved to include intensified therapy. OBJECTIVE: We assessed the association of PSA levels at 3 (PSA-3mo) and 7 (PSA-7mo) mo with overall survival (OS) in patients with mHSPC treated with ADT combined with either bicalutamide or orteronel in the S1216 phase 3 clinical trial. DESIGN, SETTING, AND PARTICIPANTS: PSA responses to treatment of patients in the S1216 trial were categorized as: complete response (CR) if PSA was ≤0.2 ng/ml, partial response if PSA was >0.2 and ≤4 ng/ml, and no response (NR) if PSA was >4 ng/ml. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A Cox analysis (adjusted for treatment arm and three stratification factors: performance status, severity of disease, and early vs late induction) was used for OS association. While PSA-7mo association was a prespecified objective, PSA-3mo association was also evaluated. RESULTS AND LIMITATIONS: A total of 1251 and 1231 patients from the S1216 study were evaluable for PSA-3mo and PSA-7mo, respectively. A PSA-7mo CR was associated with improved OS compared with NR (HR: 0.20; p < 0.0001). A PSA-3mo CR showed a similar association to NR (HR: 0.34; p < 0.0001). The association of a PSA response with survival did not differ by treatment arm at either time point. CONCLUSIONS: The PSA-3mo and PSA-7mo responses were strongly associated with OS; taken with other emerging prognostic biomarkers, these markers may allow for early identification of patients at the highest risk of death, aid with counseling in clinical practice, and permit design of future clinical trials targeting these patients. PATIENT SUMMARY: A low prostate-specific antigen level at 3 or 7 mo after starting treatment for metastatic hormone-sensitive prostate cancer predicts longer survival regardless of the first treatment given with androgen deprivation therapy.

Markers of bone metabolism and overall survival in men with bone-metastatic hormone sensitive prostate cancer (HSPC): A subset analysis of SWOG S1216, a phase III trial of androgen deprivation with or without orteronel.

BACKGROUND: Circulating biomarkers of bone metabolism are significantly associated with overall survival (OS) in men with advanced prostate cancer. In the SWOG S1216 phase III trial, we showed that elevated bone biomarkers are significantly associated with an increased risk of death in hormone-sensitive prostate cancer (HSPC) regardless of the status of bone metastases, identifying three risk groups with differential OS outcomes based on bone biomarker status. Here we report the association of bone biomarkers with OS in men with HSPC and documented skeletal metastases as part of a planned subset analysis of S1216. METHODS: Bone resorption [C-telopeptide (CTx); Pyridinoline (PYD)] and bone formation markers [C-terminal collagen propeptide (CICP); bone alkaline phosphatase (BAP)] were assessed in blood from men with bone metastatic HSPC. Patients were randomly divided into training (n = 238) and validation (n = 475) sets. In the training set, recursive partitioning that maximizes discrimination of OS was used to identify the dichotomous cut-point for each biomarker and for a combination of biomarker split points to define prognostic groups. In the validation set, Cox proportional hazards models were used to assess the impact of biomarkers on OS, adjusted for patient and tumor characteristics. RESULTS: Of 1279 men, 713 had both baseline bone metastases and evaluable bone biomarkers. Patient characteristics were similar between the overall population and the subset with bone metastases. Elevated levels of CICP, CTX, and PYD were strongly prognostic for OS. Hazard ratios (95% CI) for OS adjusted for treatment arm and baseline clinical variables were: BAP-1.31 (0.93, 1.84), p = 0.12; CICP-1.58 (1.09, 2.29), p < 0.02; CTx - 1.55 (1.12, 2.15), p = 0.008; and PYD-1.66 (1.27, 2.217), p = 0.0002. There was no evidence of interaction between elevated biomarkers and treatment (all p > 0.2). Recursive partitioning algorithms identified four groups of patients with differential OS outcomes based on bone biomarkers, adjusted for baseline clinical variables, with median OS ranging from 2.3 years (highest risk group) to 7.5 years (lowest risk group). CONCLUSIONS: In this planned S1216 subset analysis of men with HSPC and bone metastases, elevated serum markers of bone metabolism were significantly associated with worse OS. Bone biomarker levels alone and in combination with patient and tumor characteristics identify unique subsets of men with differential OS outcomes. GOV IDENTIFIER: NCT01809691.

Radiographic Progression-Free Survival and Clinical Progression-Free Survival as Potential Surrogates for Overall Survival in Men With Metastatic Hormone-Sensitive Prostate Cancer.

PURPOSE: Despite major increases in the longevity of men with metastatic hormone-sensitive prostate cancer (mHSPC), most men still die of prostate cancer. Phase III trials assessing new therapies in mHSPC with overall survival (OS) as the primary end point will take approximately a decade to complete. We investigated whether radiographic progression-free survival (rPFS) and clinical PFS (cPFS) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite future phase III clinical trials. METHODS: We obtained individual patient data (IPD) from 9 eligible randomized trials comparing treatment regimens (different androgen deprivation therapy [ADT] strategies or ADT plus docetaxel in the control or research arms) in mHSPC. rPFS was defined as the time from random assignment to radiographic progression or death from any cause whichever occurred first; cPFS was defined as the time from random assignment to the date of radiographic progression, symptoms, initiation of new treatment, or death, whichever occurred first. We implemented a two-stage meta-analytic validation model where conditions of patient-level and trial-level surrogacy had to be met. We then computed the surrogate threshold effect (STE). RESULTS: IPD from 6,390 patients randomly assigned from 1994 to 2012 from 13 units were pooled for a stratified analysis. The median OS, rPFS, and cPFS were 4.3 (95% CI, 4.2 to 4.5), 2.4 (95% CI, 2.3 to 2.5), and 2.3 years (95% CI, 2.2 to 2.4), respectively. The STEs were 0.80 and 0.81 for rPFS and cPFS end points, respectively. CONCLUSION: Both rPFS and cPFS appear to be promising surrogate end points for OS. The STE of 0.80 or higher makes it viable for either rPFS or cPFS to be used as the primary end point that is surrogate for OS in phase III mHSPC trials with testosterone suppression alone as the backbone therapy and would expedite trial conduct.

Metastatic Hormone-Sensitive Prostate Cancer in the Era of Doublet and Triplet Therapy.

OPINION STATEMENT: Treatment for metastatic hormone-sensitive prostate cancer has undergone significant evolution in recent years, leading to substantial improvements in overall survival. Men are living longer than ever before with a median survival now which is almost 6 years. The timing and extent of metastatic disease combined with individual patient factors helps treatment recommendation of doublet therapy including androgen deprivation (ADT) plus either chemotherapy or androgen receptor signaling inhibition (ARSI) or triplet therapy with ADT+ARSI+chemotherapy. New treatments must continue to be developed to enhance survival with goals of cure. Better biomarkers that allow for more effective treatments will enhance disease control, quality of life, and survival.

Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial.

Olaparib improved PFS and OS across subgroups of BRCA1/2mut #prostatecancer patients in the PROFOUND phase III trial.

PROMISE Registry: A prostate cancer registry of outcomes and germline mutations for improved survival and treatment effectiveness.

BACKGROUND: Recently approved treatments and updates to genetic testing recommendations for prostate cancer have created a need for correlated analyses of patient outcomes data via germline genetic mutation status. Genetic registries address these gaps by identifying candidates for recently approved targeted treatments, expanding clinical trial data examining specific gene mutations, and understanding effects of targeted treatments in the real-world setting. METHODS: The PROMISE Registry is a 20-year (5-year recruitment, 15-year follow-up), US-wide, prospective genetic registry for prostate cancer patients. Five thousand patients will be screened through an online at-home germline testing to identify and enroll 500 patients with germline mutations, including: pathogenic or likely pathogenic variants and variants of uncertain significance in genes of interest. Patients will be followed for 15 years and clinical data with real time patient reported outcomes will be collected. Eligible patients will enter long-term follow-up (6-month PRO surveys and medical record retrieval). As a virtual study with patient self-enrollment, the PROMISE Registry may fill gaps in genetics services in underserved areas and for patients within sufficient insurance coverage. RESULTS: The PROMISE Registry opened in May 2021. 2114 patients have enrolled to date across 48 US states and 23 recruiting sites. 202 patients have met criteria for long-term follow-up. PROMISE is on target with the study's goal of 5000 patients screened and 500 patients eligible for long-term follow-up by 2026. CONCLUSIONS: The PROMISE Registry is a novel, prospective, germline registry that will collect long-term patient outcomes data to address current gaps in understanding resulting from recently FDA-approved treatments and updates to genetic testing recommendations for prostate cancer. Through inclusion of a broad nationwide sample, including underserved patients and those unaffiliated with major academic centers, the PROMISE Registry aims to provide access to germline genetic testing and to collect data to understand disease characteristics and treatment responses across the disease spectrum for prostate cancer with rare germline genetic variants.

Bone Biomarkers and Subsequent Survival in Men with Hormone-sensitive Prostate Cancer: Results from the SWOG S1216 Phase 3 Trial of Androgen Deprivation Therapy with or Without Orteronel.

BACKGROUND: Bone biomarkers are strongly prognostic for overall survival (OS) in men with castration-resistant prostate cancer but not fully established for hormone-sensitive prostate cancer (HSPC). OBJECTIVE: Bone biomarkers in HSPC were prospectively evaluated as part of a phase 3 study of androgen deprivation therapy ± the CYP17 inhibitor orteronel. DESIGN, SETTING, AND PARTICIPANTS: Patients were randomly divided into training (n = 316) and validation (n = 633) sets. Recursive partitioning and Cox proportional hazard models were employed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Bone resorption (C-telopeptide and pyridinoline) and bone formation markers (C-terminal collagen propeptide and bone alkaline phosphatase) were assessed from patient sera. RESULTS AND LIMITATIONS: Of 1279 men, 949 had evaluable baseline bone biomarkers. Optimal cutoffs were identified to define elevated levels of each of the four biomarkers (all p < 0.05) that were associated with worse OS. After adjusting for clinical risk factors in the validation set, elevated bone biomarkers were statistically significantly associated with an increased risk of death (hazard ratios ranging from 1.37 to 1.92). Recursive partitioning algorithms applied to the training set identified three risk groups (low, intermediate, and poor) with differential OS outcomes (median OS: 8.2, 5.1, and 2.1 yr, respectively) based on combinations of bone biomarkers. These results were confirmed in the validation set. CONCLUSIONS: In men with HSPC initiating androgen deprivation therapy, bone biomarkers are strongly and independently prognostic for OS. Bone biomarker levels alone or in combination with clinical covariates identify unique subsets of men with differential OS outcomes. These results validate the clinical value of bone biomarker assessment in the HSPC state, extending bone biomarker utility beyond the castration-resistant state. PATIENT SUMMARY: In men with newly diagnosed metastatic prostate cancer, high levels of bone turnover biomarkers are associated with a shorter lifespan.

Updated Overall Survival by Circulating Tumor DNA Status from the Phase 3 IMvigor010 Trial: Adjuvant Atezolizumab Versus Observation in Muscle-invasive Urothelial Carcinoma.

BACKGROUND: Interim results from IMvigor010 showed an overall survival (OS) benefit for adjuvant atezolizumab (anti-PD-L1) versus observation in patients with circulating tumor DNA (ctDNA)-positive muscle-invasive urothelial carcinoma (MIUC). OBJECTIVE: To report updated OS and safety by ctDNA status. DESIGN, SETTING, AND PARTICIPANTS: This ad hoc analysis from a global, open-label, randomized, phase 3 trial (NCT02450331) included intention-to-treat (ITT) population with evaluable cycle 1 day 1 (C1D1) ctDNA samples. INTERVENTION: Atezolizumab (1200 mg every 3 wk) or observation for ≤1 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS, relapse rates, and safety by ctDNA status were assessed. RESULTS AND LIMITATIONS: Among 581 of 809 ITT patients included, 214 (37%) were ctDNA positive. Atezolizumab did not improve OS versus observation in ITT patients (hazard ratio [HR] 0.91 [95% confidence interval {CI} 0.73-1.13]; median follow-up 46.8 mo [interquartile range, 36.1-53.6]). In the observation arm, ctDNA positivity versus negativity was associated with shorter OS (HR 6.3 [95% CI 4.3-9.3]). The ctDNA positivity identified patients with an OS benefit favoring atezolizumab versus observation (HR 0.59 [95% CI 0.42-0.83]). A greater reduction in ctDNA levels with atezolizumab (C3D1) was associated with longer OS (100% clearance, 60.0 mo [95% CI 35.5-not estimable]; 50-99% reduction, 34.3 mo [95% CI 15.2-not estimable]; <50% reduction, 19.9 mo [95% CI 16.4-32.2]). The ctDNA positivity at C1D1 + C3D1 was associated with relapse with greater sensitivity than C1D1 alone (68% vs 57%). Adverse events were more frequent with atezolizumab than with observation, regardless of ctDNA status. A study limitation was its exploratory design. CONCLUSIONS: Evidence suggests that ctDNA positivity in MIUC predicts a benefit with atezolizumab. An in-progress prospective study will further evaluate these findings. PATIENT SUMMARY: Among patients with urothelial cancer after surgery, survival was poorer if tumor-derived DNA was detected in their bloodstream; these patients' survival was longer with atezolizumab versus observation. Bloodstream tumor-derived DNA may identify patients who benefit from atezolizumab.

Efficacy and Safety of Darolutamide in Combination With Androgen-Deprivation Therapy and Docetaxel in Black Patients From the Randomized ARASENS Trial.

BACKGROUND: In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (HR, 0.68; 95% CI, 0.57-0.80; P < .0001) compared with placebo plus ADT with docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We present efficacy and safety of darolutamide versus placebo in Black patients from ARASENS. PATIENTS AND METHODS: Patients with mHSPC were randomized 1:1 to darolutamide 600 mg or placebo twice daily in combination with ADT and docetaxel. The primary endpoint was overall survival. Key secondary endpoints included time to castration-resistant prostate cancer (CRPC) and safety. RESULTS: In ARASENS, 54 Black patients received darolutamide (n = 26) or placebo (n = 28) plus ADT and docetaxel. In Black patients, overall survival favored darolutamide versus placebo (median, not reached vs. 38.7 months; stratified HR, 0.41; 95% CI, 0.17-1.02), with 4-year survival rates of 62% versus 41%. The darolutamide group also had longer time to CRPC compared with the placebo group (median, not reached vs .12.6 months; HR, 0.09; 95% CI, 0.02-0.30). The safety profile of darolutamide in Black patients was consistent with that observed for the overall ARASENS population (grade 3/4 treatment-emergent adverse events, TEAEs: 61.5% vs. 66.1%; serious TEAEs: 42.3% vs. 44.8%). CONCLUSION: In this small population of Black patients with mHSPC from the ARASENS trial, darolutamide was associated with an improvement in survival and time to CRPC and was well tolerated. Efficacy and safety findings in Black patients were consistent with the overall ARASENS population.

Race and Treatment Outcomes in Patients With Metastatic Castration-Sensitive Prostate Cancer: A Secondary Analysis of the SWOG 1216 Phase 3 Trial.

Importance: Black patients present with more aggressive disease and experience higher mortality than White patients with prostate cancer. Race and social determinants of health influence prostate cancer-specific mortality and overall survival (OS); however, in a previous trial, Black patients did not have inferior outcomes compared with White patients, possibly because of equitable access to care available in a clinical trial setting. Objective: To compare differences in survival outcomes of patients with metastatic castration-sensitive prostate cancer (mCSPC) by race in a phase 3 trial with a large proportion of Black patients. Design, Setting, and Participants: This secondary analysis of patient-level data of a prospective phase 3 randomized clinical trial included patients with newly diagnosed mCSPC enrolled between March 1, 2013, and July 15, 2017. Analysis was conducted between December 2022 and February 2023. Interventions: Patients receiving androgen deprivation therapy were randomized (1:1) to receive either orteronel 300 mg orally twice daily (experimental group) or bicalutamide 50 mg orally daily (control group). Main Outcomes and Measures: OS, with progression-free survival (PFS) as a secondary end point. Results: Among 1313 participants, 135 (10%) identified as Black and 1077 (82%) as White, with an equal racial distribution between groups. Black patients were younger (median [IQR] age, 65.8 [60-70] vs 68.4 [62.5-74.1] years; P = .001) and had a higher median (IQR) baseline prostate-specific antigen response rate than White patients (54.7 [19.8-222.0] vs 26.7 [9.2-96.0] ng/mL; P < .001). At a median follow-up of 4.9 years, Black and White patients had similar median PFS (2.3 years; 95% CI, 1.8-1.4 years vs 2.9 years; 95% CI, 2.5-3.3 years; P = .71) and OS (5.5 years; 95% CI, 4.8-NR vs 6.3 years; 95% CI, 5.7-NR; P = .65). The multivariable analysis confirmed similar PFS and OS after adjusting for known prognostic factors. No interaction between race and treatment was observed. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial studying androgen deprivation therapy with first- or second-generation androgen receptor pathway inhibitors, both Black and White patients demonstrated similar OS and PFS. Equitable access to care may reduce historical differences in outcomes between Black and White patients with advanced prostate cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT01809691.

Plain language summary: Can declines in prostate-specific antigen level indicate how long patients with advanced prostate cancer will live when treated with enzalutamide?

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a research article originally published in the Journal of Urology. The PROSPER study involved men who had a type of advanced prostate cancer called non-metastatic castration-resistant prostate cancer (nmCRPC). In patients with nmCRPC, their prostate cancer keeps growing even after traditional hormone treatments. In these patients, rising prostate-specific antigen (PSA) levels suggest that cancer is active but CT and bone scans show that it has not spread to other parts of the body. Everyone in this study received androgen deprivation therapy (ADT) either with the medicine enzalutamide or a placebo. Enzalutamide is a medicine that can slow or stop androgens, such as testosterone, from making prostate cancer grow. The main results of the PROSPER study showed that patients with nmCRPC treated with enzalutamide and ADT lived longer than patients treated with placebo and ADT. In this study, researchers wanted to know if the findings were different depending on how much patients' PSA level declined after enzalutamide treatment. Researchers also wanted to know if this made a difference in how long patients lived without the cancer spreading to other parts of their body. WHAT WERE THE RESULTS?: Researchers found that patients with a large decline in PSA level after treatment were more likely to live longer and without their cancer spreading. WHAT DO THE RESULTS MEAN?: This study shows a link between PSA level changes and how long patients with nmCRPC live when treated with enzalutamide and ADT. These results may help health professionals monitor patients with different PSA level changes after enzalutamide treatment. Patients with a large decline in PSA level may not need to be monitored as closely as patients with a small decline in PSA level.

Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth.

CXCR7 is an atypical chemokine receptor that recruits ß-arrestin (ARRB2) and internalizes into clathrin-coated intracellular vesicles where the complex acts as a scaffold for cytoplasmic kinase assembly and signal transduction. Here, we report that CXCR7 was elevated in the majority of prostate cancer (PCa) cases with neuroendocrine features (NEPC). CXCR7 markedly induced mitotic spindle and cell cycle gene expression. Mechanistically, we identified Aurora Kinase A (AURKA), a key regulator of mitosis, as a novel target that was bound and activated by the CXCR7-ARRB2 complex. CXCR7 interacted with proteins associated with microtubules and golgi, and, as such, the CXCR7-ARRB2-containing vesicles trafficked along the microtubules to the pericentrosomal golgi apparatus, where the complex interacted with AURKA. Accordingly, CXCR7 promoted PCa cell proliferation and tumor growth, which was mitigated by AURKA inhibition. In summary, our study reveals a critical role of CXCR7-ARRB2 in interacting and activating AURKA, which can be targeted by AURKA inhibitors to benefit a subset of patients with NEPC.

Factor Structure of the Postpartum Bonding Questionnaire in a US-Based Cohort of Mothers.

As research efforts in the field of pediatrics are oriented toward a better understanding of the synergistic relationship between different facets of early relational health (ERH) and child development and wellbeing, it is essential to focus on the quality of research instruments available for measuring different components of ERH. This study investigates the measurement characteristics of a widely used parent/caregiver-reported measure of bonding, the Postpartum Bonding Questionnaire (PBQ), in a US-based sample (n=610) of English-speaking biological mothers who completed the PBQ at 4 months postpartum. To evaluate the factor structure of the PBQ, confirmatory and exploratory statistical techniques were employed. The current study failed to replicate the PBQ's original 4-factor structure. Exploratory factor analysis results supported the creation of a 14-item abbreviated measure, the PBQ-14. The PBQ-14 showed evidence of good psychometric properties, including high internal consistency (ω=.87) and correlation with depression (r=.44, p<.001) assessed using the Patient Health Questionnaire (PHQ-9), as would be expected. The new unidimensional PBQ-14 is suitable for use in the US as a measure of general postnatal parent/caregiver-to-infant bonding.

Metastatic Hormone-Sensitive Prostate Cancer: Toward an Era of Adaptive and Personalized Treatment.

The advent of more effective treatment combinations for metastatic hormone-sensitive prostate cancer (mHSPC) has been built on successes in therapy development for metastatic, castration-resistant prostate cancer (mCRPC). Both disease phases hold similar challenges and questions. Is there an optimal therapy sequence to maximize disease control and balance treatment burden? Are there clinical and biologically based subgroups that inform personalized and/or adaptive strategies? How can clinicians interpret data from clinical trials in the context of rapidly evolving technologies? Herein, we review the contemporary landscape of treatment for mHSPC, including disease subgroups informing both intensification and potential deintensification strategies. Furthermore, we provide current insights into the complex biology of mHSPC and discuss the potential clinical application of biomarkers to guide therapy selection and the development of novel personalized approaches.

Assessment of Neurodevelopment in Infants With and Without Exposure to Asymptomatic or Mild Maternal SARS-CoV-2 Infection During Pregnancy.

Importance: Associations between prenatal SARS-CoV-2 exposure and neurodevelopmental outcomes have substantial public health relevance. A previous study found no association between prenatal SARS-CoV-2 infection and parent-reported infant neurodevelopmental outcomes, but standardized observational assessments are needed to confirm this finding. Objective: To assess whether mild or asymptomatic maternal SARS-CoV-2 infection vs no infection during pregnancy is associated with infant neurodevelopmental differences at ages 5 to 11 months. Design, Setting, and Participants: This cohort study included infants of mothers from a single-site prospective cross-sectional study (COVID-19 Mother Baby Outcomes [COMBO] Initiative) of mother-infant dyads and a multisite prospective cohort study (Epidemiology of Severe Acute Respiratory Syndrome Coronavirus 2 in Pregnancy and Infancy [ESPI]) of pregnant individuals. A subset of ESPI participants was subsequently enrolled in the ESPI COMBO substudy. Participants in the ongoing COMBO study were enrolled beginning on May 26, 2020; participants in the ESPI study were enrolled from May 7 to November 3, 2021; and participants in the ESPI COMBO substudy were enrolled from August 2020 to March 2021. For the current analysis, infant neurodevelopment was assessed between March 2021 and June 2022. A total of 407 infants born to 403 mothers were enrolled (204 from Columbia University Irving Medical Center in New York, New York; 167 from the University of Utah in Salt Lake City; and 36 from the University of Alabama in Birmingham). Mothers of unexposed infants were approached for participation based on similar infant gestational age at birth, date of birth, sex, and mode of delivery to exposed infants. Exposures: Maternal symptomatic or asymptomatic SARS-CoV-2 infection. Main Outcomes and Measures: Infant neurodevelopment was assessed using the Developmental Assessment of Young Children, second edition (DAYC-2), adapted for telehealth assessment. The primary outcome was age-adjusted standard scores on 5 DAYC-2 subdomains: cognitive, gross motor, fine motor, expressive language, and receptive language. Results: Among 403 mothers, the mean (SD) maternal age at delivery was 32.1 (5.4) years; most mothers were of White race (240 [59.6%]) and non-Hispanic ethnicity (253 [62.8%]). Among 407 infants, 367 (90.2%) were born full term and 212 (52.1%) were male. Overall, 258 infants (63.4%) had no documented prenatal exposure to SARS-CoV-2 infection, 112 (27.5%) had confirmed prenatal exposure, and 37 (9.1%) had exposure before pregnancy or at an indeterminate time. In adjusted models, maternal SARS-CoV-2 infection during pregnancy was not associated with differences in cognitive (ß = 0.31; 95% CI, -2.97 to 3.58), gross motor (ß = 0.82; 95% CI, -1.34 to 2.99), fine motor (ß = 0.36; 95% CI, -0.74 to 1.47), expressive language (ß = -1.00; 95% CI, -4.02 to 2.02), or receptive language (ß = 0.45; 95% CI, -2.15 to 3.04) DAYC-2 subdomain scores. Trimester of exposure and maternal symptom status were not associated with DAYC-2 subdomain scores. Conclusions and Relevance: In this study, results of a novel telehealth-adapted observational neurodevelopmental assessment extended a previous finding of no association between prenatal exposure to maternal SARS-CoV-2 infection and infant neurodevelopment. Given the widespread and continued high prevalence of COVID-19, these data offer information that may be helpful for pregnant individuals who experience asymptomatic or mild SARS-CoV-2 infections.