The Role of Tumor and Host Microbiome on Immunotherapy Response in Urologic Cancers.

Introduction & Objective: The role of the microbiome in the development and treatment of genitourinary malignancies is just starting to be appreciated. Accumulating evidence suggests that the microbiome can modulate immunotherapy through signaling in the highly dynamic tumor microenvironment. Nevertheless, much is still unknown about the immuno-oncology-microbiome axis, especially in urologic oncology. The objective of this review is to synthesize our current understanding of the microbiome's role in modulating and predicting immunotherapy response to genitourinary malignancies. Methods: A literature search for peer-reviewed publications about the microbiome and immunotherapy response in bladder, kidney, and prostate cancer was conducted. All research available in PubMed, Google Scholar, clinicaltrials.gov, and bioRxiv up to September 2023 was analyzed. Results: Significant differences in urinary microbiota composition have been found in patients with genitourinary cancers compared to healthy controls. Lactic acid-producing bacteria, such as Bifidobacterium and Lactobacillus genera, may have value in augmenting BCG responsiveness to bladder cancer. BCG may also be a dynamic regulator of PD-L1. Thus, the combination of BCG and immune checkpoint inhibitors may be an effective strategy for bladder cancer management. In advanced renal cell carcinoma, studies show that recent antibiotic administration negatively impacts survival outcomes in patients undergoing immunotherapy, while administration of CBM588, a live bacterial product, is associated with improved progression-free survival. Specific bacterial taxa, such as Streptococcus salivarius, have been linked with response to pembrolizumab in metastatic castrate-resistant prostate cancer. Fecal microbiota transplant has been shown to overcome resistance and reduce toxicity to immunotherapy; it is currently being investigated for both kidney and prostate cancers. Conclusions: Although the exact mechanism is unclear, several studies identify a symbiotic relationship between microbiota-centered interventions and immunotherapy efficacy. It is possible to improve immunotherapy responsiveness in genitourinary malignancies using the microbiome, but further research with more standardized methodology is warranted.

Prostate-Specific Membrane Antigen PET Response Associates with Metastasis-Free Survival After Stereotactic Ablative Radiation in Oligometastatic Prostate Cancer.

Purpose: Emerging data suggest that metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) can detect occult metastatic disease, and PSMA response has been proposed as a biomarker for treatment response. Herein, we identify and validate a PSMA-PET biomarker for metastasis-free survival (MFS) following MDT in omCSPC. Methods and Materials: We performed an international multi-institutional retrospective study of patients with omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation who underwent PSMA-PET/computed tomography (CT) before and after (median, 6.2 months; range, 2.4-10.9 months) treatment. Pre- and post-MDT PSMA-PET/CT maximum standardized uptake value (SUVmax) was measured for all lesions, and PSMA response was defined as the percent change in SUVmax of the least responsive lesion. PSMA response was both evaluated as a continuous variable and dichotomized into PSMA responders, with a complete/partial response (at least a 30% reduction in SUVmax), and PSMA nonresponders, with stable/progressive disease (less than a 30% reduction in SUVmax). PSMA response was correlated with conventional imaging-defined metastasis-free survival (MFS) via Kaplan-Meier and Cox regression analysis. Results: A total of 131 patients with 261 treated metastases were included in the analysis, with a median follow-up of 29 months (IQR, 18.5-41.3 months). After stereotactic ablative radiation, 70.2% of patients were classified as PSMA responders. Multivariable analysis demonstrated that PSMA response as a continuous variable was associated with a significantly worse MFS (hazard ratio = 1.003; 95% CI, 1.001-1.006; P = .016). Patients classified as PSMA responders were found to have a significantly improved median MFS of 39.9 versus 12 months (P = .001) compared with PSMA nonresponders. Our study is limited as it is a retrospective review of a heterogenous population. Conclusions: After stereotactic ablative radiation, PSMA-PET response appears to be a radiographic biomarker that correlates with MFS in omCSPC. This approach holds promise for guiding clinical management of omCSPC and should be validated in a prospective setting.

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.

Functional impairment is associated with medical debt in male cancer survivors and credit card debt in female cancer survivors.

PURPOSE: To examine the associations of functional limitations with medical and credit card debt among cancer survivor families and explore sex differences in these associations. METHODS: This cross-sectional study used data from the 2019 wave of the Panel Study of Income Dynamics, a nationally representative, population-based survey of individuals and households in the US administered in both English and Spanish and includes all households where either the head of household or spouse/partner reported having been diagnosed with cancer. Participants reported on functional limitations in six instrumental activities of daily living (IADL) and seven activities of daily living (ADL). Functional impairment was categorized as 0, 1-2 and ≥ 3 limitations. Medical debt was defined as self-reported unpaid medical bills. Credit card debt was defined as revolving credit card debt. Multivariable logistic regression analyses were performed. RESULTS: Credit card debt was more common than medical debt (39.8% vs. 7.6% of cancer survivor families). Families of male cancer survivors were 7.3 percentage points more likely to have medical debt and 16.0 percentage points less likely to have credit card debt compared to families of female cancer survivors. Whereas male cancer survivors with increasing levels of impairment were 24.7 percentage point (p-value = 0.006) more likely to have medical debt, female survivors with more functional impairment were 13.6 percentage points (p-value = 0.010) more likely to have credit card debt. CONCLUSIONS: More research on medical and credit card debt burden among cancer survivors with functional limitations is needed.

Feasibility and Acceptability of an Online Oncologist Training to Optimize Oncologist-Patient Communication and Value-Concordant Care in Advanced Cancer.

Introduction: This pilot study tested the feasibility and acceptability of a low-resource-intensive scalable online communication training designed to improve oncologists' skills in prognostic and value-concordant care discussions with advanced cancer patients. Methods: The training consisted of on-demand videos on how to convey prognostic information, manage patient emotions, and elicit patient values and incorporate these values into treatment decision making. Post-intervention, oncologists reported on their perceptions of the training. Results: Fifteen oncologists were enrolled, of whom, 13 completed the training, and 14 completed post-intervention interviews. Most oncologists reported the intervention was acceptable: 92.9% indicated the intervention was "moderately" to "very helpful"; 78.6% rated it as "somewhat" to "very much" impactful on their communication with patients. Conclusions: The present self-paced online communication training was acceptable to oncologists, supporting additional research, including evaluating intervention efficacy for improving oncologists' communication skills and value-concordant care in advanced cancer.

Chromophobe Renal Cell Carcinoma with Sarcomatoid Differentiation.

Chromophobe renal cell carcinoma (chRCC) is one of the less common types of kidney cancer and generally portends a more favorable prognosis. RCC with sarcomatoid differentiation has a more aggressive clinical course with poor outcomes. Four cases of chRCC with varying degrees of sarcomatoid differentiation were retrospectively reviewed at our institution, and clinicopathologic data as well as clinical courses were reported. Patients with higher degrees of sarcomatoid differentiation and larger tumors at presentation generally had and worse overall survival. chRCC with sarcomatoid differentiation portends a poor prognosis with limited data on systemic treatment options for metastatic disease.

Facilitating psychological adjustment for breast cancer patients through empathic communication and uncertainty reduction.

OBJECTIVES: This study examined the degree to which breast cancer patients' psychological well-being is facilitated through empathic provider communication. We explored symptom/prognostic uncertainty reduction as a mechanism through which provider communication influences patient psychological adjustment. Additionally, we tested if treatment status moderates this relationship. METHODS: Informed by uncertainty in illness theory, current (n = 121) and former (n = 187) breast cancer patients completed questionnaires about perceptions of their oncologists' empathy and their symptom burden, uncertainty, and adjustment to their diagnosis. Structural equation modeling (SEM) was conducted to test hypothesized relationships between perceived provider empathic communication, uncertainty, symptom burden, and psychological adjustment. RESULTS: SEM supported the following: (1) higher symptom burden was associated with increased uncertainty and reduced psychological adjustment, (2) lower uncertainty was associated with increased adjustment, and (3) increased empathic communication was associated with lower symptom burden and uncertainty for all patients (χ2(139) = 307.33, p < .001; RMSEA = .063 (CI .053, .072); CFI = .966; SRMR = .057). Treatment status moderated these relationships (Δχ2 = 264.07, Δdf = 138, p < .001) such that the strength of the relationship between uncertainty and psychological adjustment was stronger for former patients than for current patients. CONCLUSIONS: Results of this study reinforce the importance of perceptions of provider empathic communication as well as the potential benefits of eliciting and addressing patient uncertainty about treatment and prognosis throughout the cancer care continuum. PRACTICE IMPLICATIONS: Patient uncertainty should be a priority for cancer-care providers both throughout and post-treatment for breast cancer patients.

Metastasis-Directed Therapy for Oligometastatic Castration-Sensitive Prostate Cancer: An Alternative to ADT?

PURPOSE OF REVIEW: The standard treatment of patients with metastatic prostate cancer is systemic treatment with androgen-deprivation therapy (ADT). The spectrum-based model of metastatic disease includes the presence of an oligometastatic state, an intermediary between localized and widespread metastatic disease, in which radical local treatment might improve systemic control. Our purpose is to review the literature on metastasis-directed therapy in the treatment of oligometastatic prostate cancer. RECENT FINDINGS: Several prospective clinical trials have reported improvements in ADT-free survival and progression-free survival with metastasis-directed therapy of oligometastatic prostate cancer. Retrospective studies have found improvements in oncologic outcomes for patients with oligometastatic prostate cancer undergoing metastasis-directed therapy, and several recent prospective clinical trials have confirmed these results. Advancements in imaging as well as an understanding of the genomics of oligometastatic prostate cancer may allow for better patient selection for metastasis-directed therapy and the potential for cure in selected patients.

Factors associated with clinical trial participation for patients with renal cell carcinoma.

OBJECTIVE: Recruitment of a diverse and representative study population is critical to the external validity of oncology clinical trials. The primary objective of this study was to characterize the factors associated with clinical trial participation for patients with renal cell carcinoma and the secondary objective was to examine differences in survival outcomes. MATERIALS AND METHODS: We used a matched case-control design by querying the National Cancer Database for patients with renal cell carcinoma who were coded as having enrolled in a clinical trial. Trial patients were matched in a 1:5 ratio to the control cohort based on clinical stage and then sociodemographic variables were compared between the 2 groups. Multivariable conditional logistic regression models evaluated factors associated with clinical trial participation. The trial patient cohort was then matched again in a 1:10 ratio based on age, clinical stage, and comorbidities. Log-rank test was used to compare overall survival (OS) between these groups. RESULTS: From 2004 to 2014, 681 patients enrolled in clinical trials were identified. Clinical trial patients were significantly younger and had a lower Charlson-Deyo comorbidity score. On multivariate analysis, male patients and white patients were more likely to participate compared to their Black counterparts. Having Medicaid or Medicare negatively associated with trial participation. Median OS was greater among clinical trial participants. CONCLUSION: Patient sociodemographic factors remain significantly associated with clinical trial participation and trial participants experienced superior OS to their matched counterparts.

Pilot Study Evaluating Cross-Disciplinary Educational Material to Improve Patients' Knowledge of Palliative Radiation Therapy.

Palliative radiation therapy (PRT) is underutilized, partially due to misconceptions about its risks, benefits, and indications. The objective of this pilot study was to determine if patients with metastatic cancer would gain knowledge from educational material describing PRT and perceive it as useful in their care. A one-page handout conveying information about the purpose, logistics, benefits, risks, and common indications for PRT was offered to patients undergoing treatment for incurable, metastatic solid tumors in one palliative care clinic and four medical oncology clinics. Participants read the handout, then completed a questionnaire assessing its perceived value. Seventy patients participated between June and December 2021. Sixty-five patients (93%) felt they learned from the handout (40% learned "lots"), and 69 (99%) felt the information was useful (53% "very useful"). Twenty-one patients (30%) were previously unaware that PRT can relieve symptoms, 55 (79%) were unaware that PRT can be delivered in five treatments or less, and 43 (61%) were unaware that PRT usually has few side effects. Sixteen patients (23%) felt they currently had symptoms not being treated well enough, and 34 (49%) felt they had symptoms that radiation might help with. Afterwards, most patients felt more comfortable bringing symptoms to a medical oncologist's (n = 57, 78%) or radiation oncologist's (n = 51, 70%) attention. Patient-directed educational material about PRT, provided outside of a radiation oncology department, was perceived by patients as improving their knowledge and adding value in their care, independent of prior exposure to a radiation oncologist.

Psychological Determinants of Physician Variation in End-of-Life Treatment Intensity: A Systematic Review and Meta-Synthesis.

BACKGROUND: Physicians treating similar patients in similar care-delivery contexts vary in the intensity of life-extending care provided to their patients at the end-of-life. Physician psychological propensities are an important potential determinant of this variability, but the pertinent literature has yet to be synthesized. OBJECTIVE: Conduct a review of qualitative studies to explicate whether and how psychological propensities could result in some physicians providing more intensive treatment than others. METHODS: Systematic searches were conducted in five major electronic databases-MEDLINE ALL (Ovid), Embase (Elsevier), CINAHL (EBSCO), PsycINFO (Ovid), and Cochrane CENTRAL (Wiley)-to identify eligible studies (earliest available date to August 2021). Eligibility criteria included examination of a physician psychological factor as relating to end-of-life care intensity in advanced life-limiting illness. Findings from individual studies were pooled and synthesized using thematic analysis, which identified common, prevalent themes across findings. RESULTS: The search identified 5623 references, of which 28 were included in the final synthesis. Seven psychological propensities were identified as influencing physician judgments regarding whether and when to withhold or de-escalate life-extending treatments resulting in higher treatment intensity: (1) professional identity as someone who extends lifespan, (2) mortality aversion, (3) communication avoidance, (4) conflict avoidance, (5) personal values favoring life extension, (6) decisional avoidance, and (7) over-optimism. CONCLUSIONS: Psychological propensities could influence physician judgments regarding whether and when to de-escalate life-extending treatments. Future work should examine how individual and environmental factors combine to create such propensities, and how addressing these propensities could reduce physician-attributed variation in end-of-life care intensity.

A Phase I Study of Combination Olaparib and Radium-223 in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) with Bone Metastases (COMRADE).

Given that radium-223 is a radiopharmaceutical that induces DNA damage, and olaparib is a PARP inhibitor that interferes with DNA repair mechanisms, we hypothesized their synergy in metastatic castration-resistant prostate cancer (mCRPC). We sought to demonstrate the safety and efficacy of olaparib + radium-223. We conducted a multicenter phase I 3+3 dose escalation study of olaparib with fixed dose radium-223 in patients with mCRPC with bone metastases. The primary objective was to establish the RP2D of olaparib, with secondary objectives of safety, PSA response, alkaline phosphatase response, radiographic progression-free survival (rPFS), overall survival, and efficacy by homologous recombination repair (HRR) gene status. Twelve patients were enrolled; all patients received a prior androgen receptor signaling inhibitor (ARSI; 100%) and 3 patients (25%) prior docetaxel. Dose-limiting toxicities (DLT) included cytopenias, fatigue, and nausea. No DLTs were seen in the observation period however delayed toxicities guided the RP2D. The RP2D of olaparib was 200 mg orally twice daily with radium-223. The most common treatment-related adverse events were fatigue (92%) and anemia (58%). The rPFS at 6 months was 58% (95% confidence interval, 27%-80%). Nine patients were evaluable for HRR gene status; 1 had a BRCA2 alteration (rPFS 11.8 months) and 1 had a CDK12 alteration (rPFS 3.1 months). Olaparib can be safely combined with radium-223 at the RP2D 200 mg orally twice daily with fixed dose radium-223. Early clinical benefit was observed and will be investigated in a phase II study.

Palliative Care Interventions Effects on Psychological Distress: A Systematic Review & Meta-Analysis.

BACKGROUND: Managing psychological distress is an objective of palliative care. No meta-analysis has evaluated whether palliative care reduces psychological distress. OBJECTIVES: Examine the effects of palliative care on depression, anxiety, and general psychological distress for adults with life-limiting illnesses and their caregivers. DESIGN: We searched PubMed, PsycInfo, Embase, and CINAHL for randomized clinical trials (RCTs) of palliative care interventions. RCTs were included if they enrolled adults with life-limiting illnesses or their caregivers, reported data on psychological distress at 3 months after study intake, and if authors had described the intervention as "palliative care." RESULTS: We identified 38 RCTs meeting our inclusion criteria. Many (14/38) included studies excluded participants with common mental health conditions. There were no statistically significant improvements in patient or caregiver anxiety (patient SMD: -0.008, P = 0.96; caregiver SMD: -0.21, P = 0.79), depression (patient SMD: -0.13, P = 0.25; caregiver SMD -0.27, P = 0.08), or psychological distress (patient SMD: 0.26, P = 0.59; caregiver SMD: 0.04, P = 0.78). CONCLUSIONS: Psychological distress is not likely to be reduced in the context of a typical palliative care intervention. The systemic exclusion of patients with common mental health conditions in more than 1/3 of the studies raises ethical questions about the goals of palliative care RCTS and could perpetuate inequalities.

Breaking bad news: during the holiday season.

Breaking bad news can be a difficult process. This can further be complicated when such news needs to be delivered around the holiday season. Here, we discuss such a case, and provide recommendations on breaking bad news around the holiday season.

Top Ten Tips Palliative Care Clinicians Should Know About Urological Care.

Patients receiving palliative care (PC) can present with or develop a host of urological needs or complications. These needs can include attention to sexual health, urinary incontinence, genitourinary bleeding, and urinary tract obstruction by benign, malignant, or urinary stone diseases. These varied conditions require that PC clinicians understand invasive and noninvasive medical, surgical, and radiation options for treatment. This article, written by a team of urologists, geriatricians, and PC specialists, offers information and guidance to PC teams in an accessible "Top Ten Tips" format to increase comfort with and skills around assessment, evaluation, and specialist referral for urological conditions common in the PC setting.

Disease and debt: Findings from the 2019 Panel Study of Income Dynamics in the United States.

Medical debt has grown dramatically over the past few decades. While cancer and diabetes are known to be associated with medical debt, little is known about the impact of other medical conditions and health behaviors on medical debt. We analyzed cross-sectional data on 9174 households - spanning lower-income, middle-income, and higher-income based on the Census poverty threshold - participating in the 2019 wave of the nationally representative United States Panel Study of Income Dynamics (PSID). The outcomes were presence of any medical debt and presence of medical debt≥ $2000. Respondents reported on medical conditions (diabetes, cancer, heart disease, chronic lung disease, asthma, arthritis, anxiety disorders, mood disorders) and on health behaviors (smoking, heavy drinking). Medical debt was observed in lower-income households with heart disease (OR = 2.64, p-value = 0.006) and anxiety disorders (OR = 2.16, p-value = 0.02); middle-income households with chronic lung disease (OR = 1.73, p-value = 0.03) and mood disorders (OR = 1.53, p-value = 0.04); and higher-income households with a current smoker (OR = 2.99, p-value<0.001). Additionally, medical debt ≥$2000 was observed in lower-income households with asthma (OR = 2.16, p-value = 0.009) and a current smoker (OR = 1.62, p-value = 0.04); middle income households with hypertension (OR = 1.65, p-value = 0.05). These novel findings suggest that the harms of medical debt extend beyond cancer, diabetes and beyond lower-income households. There is an urgent need for policy and health services interventions to address medical debt in a wider range of disease contexts than heretofore envisioned. Intervention development would benefit from novel conceptual frameworks on the causal relationships between health behaviors, health conditions, and medical debt that center social-ecological influences on all three of these domains.

Renal Cell Carcinoma with Cardiac Metastases: A Case Report and Review of the Literature.

Cardiac metastases from renal cell carcinoma (RCC) are very rare. We describe the case of a woman with RCC with cardiac metastases involving the entire right atrium, penetrating through the myocardium, with extension into the tricuspid valve and right ventricle. This report highlights the unique challenge of the diagnosis and treatment of cardiac metastases in RCC.

A phase Ib dose-escalation study of troriluzole (BHV-4157), an oral glutamatergic signaling modulator, in combination with nivolumab in patients with advanced solid tumors.

BACKGROUND: Glutamate signaling activates MAPK and PI3K/AKT pathways in tumor cells. Treatment with riluzole, a glutamate release inhibitor, has been previously shown to be safe in melanoma patients and produced biologic effects, but did not lead to radiographic responses, possibly due to poor pharmacokinetic properties. Therefore, we conducted a phase Ib trial to determine the safety and tolerability of the combination of the riluzole prodrug troriluzole (BHV-4157, trigriluzole) and the PD-1 antibody nivolumab in patients with advanced solid tumors. METHODS: Patients with advanced or refractory solid tumors and measurable disease per RECIST 1.1 were treated with increasing doses of troriluzole using a semi-Bayesian modified toxicity probability interval dose escalation procedure. Troriluzole monotherapy was orally self-administered for a 14-day lead-in period followed by continuation of troriluzole in combination with nivolumab 240 mg IV every 2 weeks. Endpoints included safety, pharmacokinetics (PK) and efficacy. RESULTS: We enrolled 14 patients with advanced solid tumors (melanoma = 3, NSCLC = 3, renal cell carcinoma = 2, bladder/urothelial = 2, ovarian cancer = 1, adenoid cystic carcinoma = 1, pleural mesothelial = 1, head and neck cancer = 1). Eleven patients had cancer progression on prior therapy with PD-1 or PD-L1 agent. Patients received troriluzole total daily doses from 140 to 560 mg (divided). The most common treatment-related adverse events (TRAE) occurring in ≥ 5 patients (> 35%) were transaminitis and increased lipase. DLT (dose-limiting toxicity) occurred in 3 patients: (1) grade 3 anorexia, (2) grade 3 fatigue and, (3) grade 3 atrial fibrillation. Six patients were treated at the MTD (maximum tolerated dose). No subjects discontinued treatment due to AEs. One response occurred (7%), which was a partial response in a subject who had PD-1 refractory disease. The 6-month PFS rate was 21%. PK data showed that the prodrug troriluzole was efficiently cleaved into riluzole by 2-h post-dosing in all dose cohorts tested. CONCLUSION: The combination of troriluzole and nivolumab was safe and well-tolerated. The MTD of troriluzole was determined to be 420 mg total daily dose. The observed antitumor activity, primarily disease stabilization, is of interest in patients with PD-1 resistant tumors. Trial Registration ClinicalTrials.gov Identifier NCT03229278.

Genomic analysis and long-term outcomes of a phase 1 clinical trial on cytoreductive radical prostatectomy.

Purpose: Approximately 7% of patients with newly diagnosed prostate cancer (PCa) in the US will have have metastatic disease. The dogma that there is no role for surgery in this population has been questioned recently. Here we report long-term outcomes of a phase 1 clinical trial on cytoreductive radical prostatectomy. Materials and methods: This is a multicenter phase 1 trial. The major inclusion criterion was biopsy proven N1M0 or NxM1a/b PCa. Primary end point was the Clavien-Dindo-based major complication rate. Secondary outcomes were biochemical progression and overall survival. RNA-seq correlative study was conducted in nine select cases as a pilot study. Results: Final accrual was 32 patients of which 25 and 7 were cNxM1 and cN1M0, respectively. With the median follow-up of 46 months (interquartile range 31.7 - 52.7 months), 25 out of the 32 patients (75%) were alive at the time of last contact. There were three disparate groups based on the oncologic outcome: favorable, intermediate, and poor. In seven men with favorable response, androgen deprivation therapy was switched to intermittent approach and five remain free of any evidence of disease after more than two years off all systemic therapy with the normalization of serum testosterone. Of these five patients, three had M1 disease. Long-term use of one pad or less per day was 80%. RNA-seq analysis revealed an enriched downregulation of tumor necrosis factor (TNF)-α signature in the favorable group. Conclusion: Overall long-term oncologic outcome of cytoreductive radical prostatectomy was significantly higher than historical results. Importantly, the combination of surgery with systemic therapy may result in a long durable response in a minority of men who present with metastatic PCa.