Faculty Bibliography

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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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.

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.

PURPOSE OF REVIEW/OBJECTIVE:Next-generation sequencing is becoming more accessible. This review focuses on the clinical application of somatic and germline sequencing to genitourinary oncology. RECENT FINDINGS/RESULTS:Germline variants have been increasingly recognized as contributing to the development of genitourinary malignancies, particularly in patients with advanced disease. A variety of commercial and institutional technologies are in use to detect variants, with newer tools focused on integrating these results into the clinical workflow. SUMMARY/CONCLUSIONS:DNA sequencing is becoming a valuable tool in caring for patients with genitourinary malignancies. Performing both somatic and germline sequencing will likely become standard practice. Interpretation and clinical application of these results can be challenging and often requires multidisciplinary expertise.

Background: Metastatic castrate-resistant prostate cancer (mCRPC) remains an incurable illness as resistance develops after androgen deprivation therapy (ADT) and/or androgen receptor (AR) axis targeted therapies. The bromodomain (BRD) and extraterminal (BET) proteins are critical for transcription. Preclinically, one of these proteins, BRD4, acts in complex with AR to mediate androgen signaling that leads to prostate cell growth and proliferation. GSK525762 is an oral pan-BET inhibitor that suppresses BET dependent activated AR-driven transcription. Combined with androgen production or receptor targeted agents like abiraterone or enzalutamide, GSK525762 may enhance efficacy of or overcome resistance to either agent.
Method(s): This is a Phase IB open-label, dose-escalation study to evaluate the safety and efficacy of oral administration of GSK525762 in combination with either abiraterone plus prednisone (Arm A) or enzalutamide (Arm B) in mCRPC patients whose disease has progressed on prior abiraterone or enzalutamide. Patients must have documented prostate cancer progression as assessed by rising PSA or radiographic progression of soft tissue by PCWG3-modified RECIST 1.1 criteria or bone metastasis. Dose escalation is designed to identify safe doses to move into dose expansion. Dose expansion will explore safety and efficacy in patients who failed in first line (L2 population) or after multiple lines of prior therapy (LX population). Primary objectives include defining the safety, tolerability and clinical activity of GSK525762 when combined with products in Arm A or Arm B. Primary clinical activity endpoint is defined as the response rate of subjects achieving a 50% or more reduction from baseline of PSA at 12 weeks or thereafter. Dose escalation will employ a modified Toxicity Probability Interval (mTPI) design. Dose expansion will use a Bayesian adaptive design, which will calculate posterior probability that utility of the dose is clinically significant at interim futility analysis for each dose level.
Funding(s): GSK Clinical trial information: NCT03150056

Androgen receptor (AR) signaling is a distinctive feature of prostate carcinoma (PC) and represents the major therapeutic target for treating metastatic prostate cancer (mPC). Though highly effective, AR antagonism can produce tumors that bypass a functional requirement for AR, often through neuroendocrine (NE) transdifferentiation. Through the molecular assessment of mPCs over two decades, we find a phenotypic shift has occurred in mPC with the emergence of an AR-null NE-null phenotype. These "double-negative" PCs are notable for elevated FGF and MAPK pathway activity, which can bypass AR dependence. Pharmacological inhibitors of MAPK or FGFR repressed the growth of double-negative PCs in vitro and in vivo. Our results indicate that FGF/MAPK blockade may be particularly efficacious against mPCs with an AR-null phenotype.

Metastatic disease of the skin can be difficult to diagnose, particularly when lesions occur in unusual anatomic locations. We report the case of an 80-year-old woman with a history of anal squamous cell carcinoma (SCC) who developed genital ulcers. Biopsy of the lesions revealed features consistent with metastatic SCC. Cutaneous metastases are an infrequent cause of genital ulcerations, and it is important for physicians to consider this entity when evaluating genital ulcers in patients with prior malignancies.

UNLABELLED: Recently, there has been a renewed interest in the study of tumor metabolism above and beyond the Warburg effect. Studies on cancer cell metabolism have provided evidence that tumor-specific activation of signaling pathways, such as the upregulation of the oncogene myc, can regulate glutamine uptake and its metabolism through glutaminolysis to provide the cancer cell with a replacement of energy source. METHODS: We report a convenient procedure to prepare l-[5-(11)C]-glutamine. The tracer was evaluated in 9L and SF188 tumor cells (glioma and astrocytoma cell lines). The biodistribution of l-[5-(11)C]-glutamine in rodent tumor models was investigated by dissection and PET. RESULTS: By reacting (11)C-cyanide ion with protected 4-iodo-2-amino-butanoic ester, the key intermediate was obtained in good yield. After hydrolysis with trifluoroacetic and sulfonic acids, the desired optically pure l-[5-(11)C]-glutamine was obtained (radiochemical yield, 5% at the end of synthesis; radiochemical purity, >95%). Tumor cell uptake studies showed maximum uptake of l-[5-(11)C]-glutamine reached 17.9% and 22.5% per 100 mug of protein, respectively, at 60 min in 9L and SF188 tumor cells. At 30 min after incubation, more than 30% of the activity appeared to be incorporated into cellular protein. Biodistribution in normal mice showed that l-[5-(11)C]-glutamine had significant pancreas uptake (7.37 percentage injected dose per gram at 15 min), most likely due to the exocrine function and high protein turnover within the pancreas. Heart uptake was rapid, and there was 3.34 percentage injected dose per gram remaining at 60 min after injection. Dynamic small-animal PET studies in rats bearing xenografted 9L tumors and in transgenic mice bearing spontaneous mammary gland tumors showed a prominent tumor uptake and retention. CONCLUSION: The data demonstrated that this tracer was favorably taken up in the tumor models. The results suggest that l-[5-(11)C]-glutamine might be useful for probing in vivo tumor metabolism in glutaminolytic tumors.

Oncogenic Myc alters mitochondrial metabolism, making it dependent on exogenous glutamine (Gln) for cell survival. Accordingly, Gln deprivation selectively induces apoptosis in MYC-overexpressing cells via unknown mechanisms. Using MYCN-amplified neuroblastoma as a model, we identify PUMA, NOXA, and TRB3 as executors of Gln-starved cells. Gln depletion in MYC-transformed cells induces apoptosis through ATF4-dependent, but p53-independent, PUMA and NOXA induction. MYC-transformed cells depend on both glutamate-oxaloacetate transaminase and glutamate dehydrogenase to maintain Gln homeostasis and suppress apoptosis. Consequently, either ATF4 agonists or glutaminolysis inhibitors potently induce apoptosis in vitro and inhibit tumor growth in vivo. These results reveal mechanisms whereby Myc sensitizes cells to apoptosis, and validate ATF4 agonists and inhibitors of Gln metabolism as potential Myc-selective cancer therapeutics.