Faculty Bibliography

BACKGROUND:TMPRSS2, a cell surface protease regulated by androgens and commonly upregulated in prostate cancer (PCa), is a necessary component for SARS-CoV-2 viral entry into respiratory epithelial cells. Previous reports suggested a lower risk of SARS-CoV-2 among PCa patients on androgen deprivation therapy (ADT). However, the impact of ADT on severe COVID-19 illness is poorly understood. METHODS:We performed a multicenter study across 7 US medical centers and evaluated patients with PCa and SARS-CoV-2 detected by polymerase-chain-reaction between March 1, 2020, and May 31, 2020. PCa patients were considered on ADT if they had received appropriate ADT treatment within 6 months of COVID-19 diagnosis. We used multivariable logistic and Cox proportional-hazard regression models for analysis. All statistical tests were 2-sided. RESULTS:We identified 465 PCa patients (median age = 71 years) with a median follow-up of 60 days. Age, body mass index, cardiovascular comorbidity, and PCa clinical disease state adjusted overall survival (hazard ratio [HR] = 1.16, 95% confidence interval [CI] = 0.68 to 1.98, P = .59), hospitalization status (HR = 0.96, 95% CI = 0.52 to 1.77, P = .90), supplemental oxygenation (HR 1.14, 95% CI = 0.66 to 1.99, P = .64), and use of mechanical ventilation (HR = 0.81, 95% CI = 0.25 to 2.66, P = .73) were similar between ADT and non-ADT cohorts. Similarly, the addition of androgen receptor-directed therapy within 30 days of COVID-19 diagnosis to ADT vs ADT alone did not statistically significantly affect overall survival (androgen receptor-directed therapy: HR = 1.27, 95% CI = 0.69 to 2.32, P = .44). CONCLUSIONS:In this retrospective cohort of PCa patients, the use of ADT was not demonstrated to influence severe COVID-19 outcomes, as defined by hospitalization, supplemental oxygen use, or death. Age 70 years and older was statistically significantly associated with a higher risk of developing severe COVID-19 disease.

Background: The germline I1307K mutation in the adenomatous polyposis coli (APC) gene is a well known alteration identified in approximately 6% of the Ashkenazi Jewish population. Individuals with this mutation have an increased risk of developing colorectal and other cancers. The implications of the APC (I1307K) mutation in patients with prostate cancer are unknown. We sought to determine the clinical outcomes of patients with prostate cancer and the germline APC (I1307K) mutation.
Method(s): We retrospectively reviewed records from New York University and Johns Hopkins University to identify patients with the APC (I1307K) mutation. Eligibility criteria included the identification of the mutation either on germline or somatic tissue testing (when germline testing was not available). Aggressive variant prostate cancer (AVPC) was defined using previously established criteria including: presence of small cell histology, presence of exclusively visceral metastases, bulky prostate mass or lymphadenopathy, low PSA with high-volume ( > 20) bone metastases, neuroendocrine marker positivity or short interval ( < 6 months) to castration resistance. Combined somatic alterations in two or more of following genes were assessed: RB1, TP53, PTEN. These somatic alterations have been previously associated with AVPC. Descriptive statistics were used to summarize patient data.
Result(s): From 2016-2021, 13 patients with the germline APC (I1307K) mutation were identified. At the time of analysis 9 (69%) patients were alive. Most patients (7; 54%) had metastatic disease at presentation. Median PSA at diagnosis was 0.4 ng/mL (range: 0.4-20 ng/mL). The median time to castration resistance among those receiving hormonal therapy was 9 months (range: 3-13 months). Presence of small cell histology was found on initial biopsy in 3 patients and on subsequent biopsy in 1 additional patient (31% overall). Bulky prostate mass or lymphadenopathy was found in 3 (23%) patients. There were 2 (15%) patients who had low PSA with high-volume bone metastases. Four (31%) patients had radiographic progression with no concordant PSA increase. Clinically-defined AVPC was found in 7 (54%) patients and in 100% of those patients with metastatic disease. Combined somatic alterations in two or more of RB1, TP53 or PTEN were identified in 3 (23%) patients.
Conclusion(s): Prostate cancers that develop in the presence of the germline APC (I1307K) mutation appear to be enriched for clinically-defined and molecularly-defined AVPC. Several of these patients demonstrated small cell histology and PSA-independent progression, higher than the expected background rate. This raises the hypothesis that the germline APC (I1307K) mutation influences the somatic genomic and/or epigenomic landscape of prostate cancer. Larger studies to validate the increased risk of AVPC in APC (I1307K) carriers, and to elucidate the somatic alteration landscape in these patients, are ongoing

Background : Cancer and peripheral artery disease (PAD) share common risk factors and are frequently coprevalent. Platelets are culprits in the pathogenesis of PAD and mediators of arterial cardiovascular events. The association between platelet activity and cardiovascular events in patients with versus without cancer is uncertain. Aims : To investigate if cancer history is associated with platelet activity and incident cardiovascular events in a cohort of patients with PAD. Methods : 289 patients with PAD undergoing lower extremity revascularization enrolled in the Platelet Activity and Cardiovascular Events (PACE) study were followed longitudinally for a median of 18 months. Prior to revascularization, patients had platelet activity measured via light transmission aggregometry in response to ADP, collagen, epinephrine, and serotonin. The primary clinical outcome was myocardial infarction (MI). Other endpoints were MI/stroke and major adverse cardiovascular event (MACE; MI/stroke/death). Results : 64 patients (22.1%) reported a cancer history, 10 (15.6%) with metastatic and 10 (15.6%) with active cancer. Patients with (versus without) cancer history were older, less often Hispanic, and less frequently current smokers ( P < 0.05 for each). There was no difference in prevalent diabetes, coronary artery disease, hypertension, or antiplatelet therapy between groups. Platelet aggregation in response to submaximal ADP (0.4 muM, 1.0 muM), collagen (0.2 mug/ml, 1.0 ug/ml), and serotonin (10 muM) was higher in patients with versus without cancer history. Consistently, patients with cancer history experienced more incident MI (18.8% vs. 7.6%, P = 0.02), MI/stroke (25.0% vs. 9.3%, P = 0.002), and MACE (35.9% vs. 22.2%, P = 0.04). After adjustment for age, sex, race/ethnicity, smoking, diabetes, prior stroke, CAD, revascularization procedure, and antiplatelet therapy, patients with cancer history were at higher hazard for MI, MI/stroke, and MACE (Figure). The association between cancer and thrombotic events was most apparent in patients with metastatic and active cancer (Figure). Conclusions : In patients with PAD, cancer history was associated with increased platelet aggregation and risk for arterial thrombotic events

Background: TMPRSS2, a cell surface protease which is commonly upregulated in prostate cancer (PC) and regulated by androgens, is a necessary component for SARS-CoV2 cellular entry into respiratory epithelial cells. PC patients receiving ADT were reported to have a lower risk of SARSCoV- 2 infection. However, whether ADT may have an impact on the severity of COVID-19 illness in this population is poorly understood.
Method(s): In this study performed across 7 US medical centers, we retrospectively evaluated patients with active PC and SARS-COV-2 viral detection by PCR between 03/01/20 and 05/31/20. We collected information on demographics; medical comorbidities; medications; PC Gleason score at initial diagnosis; presence of active disease, metastases, and castration resistance; ADT use as defined by GnRH analog or antagonist within 3 months or castration levels of testosterone < 50 ng/dL within 6 months of COVID-19 diagnosis, or history of bilateral orchiectomy; active non-ADT systemic therapies including, but not limited to, androgen-receptor-targeted therapies and chemotherapy; and COVID-19-related outcomes including hospitalization, supplemental oxygen use, mechanical ventilation requirement, WHO COVID-19 ordinal scale for clinical improvement, follow-up duration, and vital status. Multivariable mixed-effect logistic regression was performed to evaluate any difference in COVID-19 clinical outcomes between patients on and not on ADT. Survival analysis was done using adjusted Cox proportion-hazards regression model. All tests were two-sided at 0.05 significance level.
Result(s): We identified 465 evaluable patients with median age of 71 (61-81) years. Median duration of follow-up was 60 (12-114.2) days. In this follow up period, there were 195 (41.9%) hospitalizations and 111 (23.9%) deaths. When adjusted for age, BMI, and PC clinical disease state, overall survival (HR 1.28 [95%CI 0.79-2.08], P = 0.32), hospitalization status (HR 1.07 [0.61-1.87], P = 0.82), supplemental oxygen use (HR 1.29 [0.77-2.17], P = 0.34), and use of mechanical ventilation (HR 1.07 [0.51-2.23], P = 0.87) were not statistically different between ADT and non-ADT cohorts. Similarly, in subgroup analysis, no statistical difference in overall survival was found between ADT and non-ADT cohorts for hospitalized patients (HR 1.42 [0.82-2.47], P = 0.21) and those receiving supplemental oxygen (HR 1.10 [0.65-1.85], P = 0.73).
Conclusion(s): In this retrospective cohort of PC patients, use of ADT prior to COVID-19 diagnosis does not protect against severe COVID-19 illness as defined by hospitalization, supplemental oxygen use, or death. Further preclinical work in understanding TMPRSS2 expression and androgen regulation in respiratory epithelial cells is needed. As well, longer clinical follow-up and additional clinical studies inclusive of prospective data are warranted to fully address this question

BACKGROUND:Germline testing is recommended for all men with metastatic prostate cancer (PCa), and for some with localized PCa meeting specific histologic or family history criteria. Germline genetic evaluation has important implications for PCa prognosis and management, as well as implications for family members and cancer screening. Despite the importance of germline evaluation, its utilization in urologic practice is unknown. MATERIALS AND METHODS/METHODS:We conducted a 32-item survey of U.S. urologists to examine knowledge of germline testing guidelines and practice patterns. It was shared through email to 6 American Urological Association sections, the Veterans Affairs Urology Mailgroup, and social media. RESULTS:Among 132 total respondents from diverse practice settings across the U.S., 12% perform germline testing, 44% refer to a genetic counselor, 11% do both, and 33% do not test/refer. Only 4% had formal education in genetics. While 98% ask about PCa family history, only 76% and 52% ask about breast and ovarian cancer. When presented with hypothetical case scenarios where germline testing is indicated, many respondents indicated they would not offer genetic counseling or testing. Younger age (p = 0,03), academic practice (p = 0.04), and specializing in PCa/oncology (p = 0.007) were significantly associated with performing or referring for germline testing. Specializing in PCa/oncology was significantly associated with recommending germline testing for all case scenarios involving metastatic PCa (p = 0.0009) CONCLUSION: Our results suggest significant gaps in knowledge of germline testing and alignment of practice with national guidelines among urologists. Germline testing education and facilitation of genetic evaluation in urologic practice is warranted.

Background: Standard of care (SOC) regimens may contribute to immunosuppression by elevating intratumoral levels of adenosine, which activates the A2a and A2b receptors (R) on immune cells. Extracellular adenosine is primarily produced by the enzyme CD73. In prostate cancer, the activity of the highly expressed protein, prostatic acid phosphatase, produces additional adenosine. AB928, which is the first clinical-stage small molecule dual antagonist of both A2aR and A2bR, is highly potent, pharmacodynamically active, and well tolerated in dose escalation studies in combination with chemo/immunotherapy. Targeting the adenosine axis in combination with SOC regimens or immunotherapy may have a more profound effect on activating and inducing sustained antitumor immunity in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC). Trial design: This is a phase (Ph) 1b/2, open-label, multicenter platform trial to evaluate the antitumor activity and safety of AB928-based combination therapy in pts with mCRPC. Eligibility for a specific treatment arm will be informed by prior anticancer therapy. Treatment arms will independently evaluate AB928 + zimberelimab (AB122; anti-PD-1 antibody) alone or in combination with an SOC backbone (enzalutamide or docetaxel) in earlier-line pts or AB928 + AB680 (CD73 inhibitor) +/- zimberelimab in later-line pts. Treatment arms will be conducted in 2 stages: Stage 1 (Ph1b) and Stage 2 (Ph2). In Ph1b, up to 15 pts will receive investigational product(s) at the single agent recommended dose with SOC per label guidance. Provided safety and futility stopping criteria are not met, further accrual in the earlier-line arms will involve randomization to SOC alone; in the later-line arms, upfront randomization to the all-experimental regimens will continue in Ph2. Investigator-assessed antitumor response (radiologic, prostate specific antigen [PSA]) will follow PCWG3 criteria. New treatment arms may be added via protocol amendment. ARC-6 is actively recruiting in the United States, and results will be shared in upcoming scientific conferences (NCT04381832). Clinical trial identification: NCT04381832. Legal entity responsible for the study: Arcus Biosciences.
Funding(s): Arcus Biosciences. Disclosure: S.K. Subudhi: Advisory/Consultancy, Research grant/Funding (self): Janssen Oncology; Advisory/Consultancy: Polaris; Advisory/Consultancy: Dendreon; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Apricity Health; Advisory/Consultancy: Amgen; Advisory/Consultancy: Bayer; Advisory/Consultancy: Exelixis; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Dava Oncology; Advisory/Consultancy: Cancer Now; Advisory/Consultancy: MEDACorp; Honoraria (self): Parker Institute of Cancer Immunotherapy; Honoraria (self): SITC. D. Wise: Advisory/Consultancy: ScientiaCME; Advisory/Consultancy: OncLIve; Advisory/Consultancy: Foundation Medicine; Honoraria (self), Advisory/Consultancy: Best Doctors; Advisory/Consultancy: Leap Therapeutics; Advisory/Consultancy: Guidepoint Consulting; Advisory/Consultancy: GLG Consulting; Advisory/Consultancy: Silverlight; Advisory/Consultancy: Alphasights; Advisory/Consultancy: Pfizer. S.T. Liu: Advisory/Consultancy: Merck; Advisory/Consultancy: Exelixis; Advisory/Consultancy: Esai; Advisory/Consultancy: Seattle Genetics. A. Chaudhry: Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Exelixis; Advisory/Consultancy: Astellas Pharma; Shareholder/Stockholder/Stock options: Novartis; Research grant/Funding (institution): Arcus Biosciences; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Abbvie; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Beigene; Research grant/Funding (institution): BerGenBio; Research grant/Funding (institution): Blueprint; Research grant/Funding (institution): Alkermes; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Gilead; Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Millennium; Research grant/Funding (institution): Basilea; Research grant/Funding (institution): IunoCare; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Novartis. J. Kim: Advisory/Consultancy: Sanofi; Advisory/Consultancy: EMD Serono; Advisory/Consultancy: Voluntis; Research grant/Funding (self): Immune Design. O. Gardner: Shareholder/Stockholder/Stock options, Full/Part-time employment: Arcus Biosciences; Shareholder/Stockholder/Stock options, Full/Part-time employment: Bellicum Pharmaceuticals; Full/Part-time employment: Aduro Biotech; Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen. H. Gilbert: Shareholder/Stockholder/Stock options, Full/Part-time employment: Arcus Biosciences; Advisory/Consultancy, Full/Part-time employment: Bellicum; Shareholder/Stockholder/Stock options, Full/Part-time employment: Roche/Genentech; Shareholder/Stockholder/Stock options: Denali; Shareholder/Stockholder/Stock options: Celgene; Shareholder/Stockholder/Stock options: BMS. M. Grady: Shareholder/Stockholder/Stock options, Full/Part-time employment: Arcus Biosciences; Full/Part-time employment: Bellicum; Full/Part-time employment: Biothera. M. Paoloni: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Arcus Biosciences; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Janssen Oncology; Advisory/Consultancy: Amgen. K. Krishnan: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Arcus Biosciences; Full/Part-time employment: Astex; Full/Part-time employment: Roche/Genentech; Full/Part-time employment: Five Prime. M. Carducci: Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Medivation; Advisory/Consultancy: Astellas; Advisory/Consultancy: Roche; Advisory/Consultancy: Abbvie; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy: Merck; Research grant/Funding (institution): EMD Serono; Research grant/Funding (institution): Exelixis; Research grant/Funding (institution): Gilead; Research grant/Funding (institution): Effector; Non-remunerated activity/ies: ECOG-ACRIN.
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Current guidelines recommend conservative management as the preferred option for most low-risk prostate cancer cases, with certain possible exceptions (age <55yr, African Americans, and high-volume grade group 1). Although previous studies have documented substantial heterogeneity in the uptake of conservative management, less is known about the underlying reason for this variation and whether it is due to guideline-concordant factors (age, race, and biopsy cancer volume). We explored variation in the use of conservative management for low-risk prostate cancer among 20 597 men diagnosed in the US Veterans Affairs health care system from 2010 to 2016. Conservative management increased substantially over this time from 51% to 76% (p< 0.001). However, there was substantial variation by facility (35-100%). Multivariable analysis revealed that patient factors included in the guidelines (e.g., age and biopsy cores), other patient factors (eg, marital status and PSA) and non-patient factors (eg, geographic region, case volume, year) were associated with conservative management use. In conclusion, even within an integrated health care system, there remains significant heterogeneity in the uptake of conservative management for low-risk prostate cancer. Both guideline-concordant factors and other factors not discussed in the guidelines were associated with conservative management use. PATIENT SUMMARY: In the US Veterans Affairs health care system the vast majority of men with low-risk prostate cancer were managed conservatively by 2016, although there was significant variation by facility. Patient factors specifically mentioned in guidelines had the greatest impact on prediction of conservative management.

Stereotactic body radiotherapy (SBRT) is an increasingly used radiation modality for the treatment of both localized and metastatic prostate cancer. Substantial data suggests that prostate cancer may be more sensitive to higher doses of radiation per fraction due to its low α/β ratio. This increased sensitivity raises important questions as to how SBRT should be combined with systemic therapy for clinically significant prostate cancer, including whether androgen deprivation therapy retains its beneficial effects when combined with SBRT. Furthermore, pre-clinical and clinical data suggest pronounced immunomodulatory effects of SBRT, including observed improvements in T cell priming and trafficking. These data support investigational strategies combining SBRT with immunotherapy. Here we aim to review the data for the use of SBRT in both the local and metastatic disease settings as well as ongoing translational and clinical research examining combinations with ADT, immunotherapy and other targeted agents.

PURPOSE/OBJECTIVE:Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets. METHODS:Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models. Epigenetic studies were carried out in a rapid autopsy cohort. RESULTS:< .0005). Growth inhibition of the human PCa model PC3 by the anti-DKK1 monoclonal antibody DKN-01 depends on the presence of NK cells in a severe combined immunodeficient xenograft mouse model. CONCLUSION/CONCLUSIONS:These results support DKK1 as a contributor to the immunosuppressive tumor microenvironment of DNPC. These data have provided the rationale for a clinical trial targeting DKK1 in mCRPC (ClinicalTrials.gov identifier: NCT03837353).