Yale Urology Research [Q2: April-June 2023]

July 28, 2023

The following is a comprehensive list of Yale Urology faculty publications for the 2nd quarter of calendar year 2023. The listing is separated into primary and secondary faculty sections, then in descending published date order. Most listed items include cite details and portions of each abstract/summary.

PRIMARY FACULTY

Jalfon MJ, Sakhalkar OV, Lokeshwar SD, Marks VA, Choksi AU, Klaassen Z, Leapman MS, Kim IY. Local Therapeutics for the Treatment of Oligo Metastatic Prostate Cancer. Curr Urol Rep. 2023 Jun 28. doi: 10.1007/s11934-023-01173-6. Epub ahead of print. PMID: 37369828.

Oligometastatic prostate cancer [OMPC] represents an intermediate stage between clinically localized and widespread metastatic disease. Diseases classified within this stage present an opportunity for localized targeting of the disease prior to progression to widespread metastases. The purpose of this review is to discuss the contemporary and emerging local therapies for the treatment of OMPC.

Sterling J, Rahman SN, Varghese A, Angulo JC, Nikolavsky D. Complications after Prostate Cancer Treatment: Pathophysiology and Repair of Post-Radiation Urethral Stricture Disease. J Clin Med. 2023 Jun 9;12(12):3950. doi: 10.3390/jcm12123950. PMID: 37373644; PMCID: PMC10299043.

Radiation therapy (RT) in the management of pelvic cancers remains a clinical challenge to urologists given the sequelae of urethral stricture disease secondary to fibrosis and vascular insults. The objective of this review is to understand the physiology of radiation-induced stricture disease and to educate urologists in clinical practice regarding future prospective options clinicians have to deal with this condition.

Ayed A, [Onofrey J]. Machine learning to predict future PSA in patients with prostate cancer managed with active surveillance. Journal of clinical oncology. 06/2023;41(16_suppl):e17098-e17098. doi: 10.1200/JCO.2023.41.16_suppl.e17098.

Harnisch BA, [Honig SC]. Infertility in the male. Male Reproduction in the Transgender Patient. 05/31/2023:525-533. doi: 10.1017/9781108937054.032.

… this fifth edition has been fully updated and revised to provide clear, didactic advice on best practice for a variety of clinical situations faced by practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice who see men with suboptimal fertility and reproductive problems. Completely restructured to include pedagogical features such as easily accessible key concepts that cement understanding and real-world use. Covering everything from foundations of anatomy and embryology, through clinical evaluation, diagnostic approaches, treatment and fertility care in context within the healthcare system and society, thrilling advances and future directions are also included. This new edition is an essential reference for all who are working in this young and rapidly evolving field.

Simmons K, Nair H, Phadke M, Motamedinia P, Singh D, Montgomery T, Dahl NK. Risk Factors for Common Kidney Stones Are Correlated with Kidney Function Independent of Stone Composition. Am J Nephrol. 2023 May 30. doi: 10.1159/000531046. Epub ahead of print. PMID: 37253348.

Changes in urine parameters are strongly correlated with eGFR regardless of stone type. Renal function may play a key role in modulating kidney stone risk factors. Strategies to mitigate stone risk may need to vary with kidney function, especially when patient urine or stone composition data is unavailable.

Honig S. (394) effects of age, body mass index (BMI) and diabetic status on testosterone levels, testosterone dosing and safety in hypogonadal men treated with an oral testosterone undecanoate (JATENZO). Journal of sexual medicine. 05/2023;20(supplement_1). doi: 10.1093/jsxmed/qdad060.368.

Regardless of age, BMI, or diabetes status, eugonadal total T levels were achieved in men administered oral TU. Age did not influence the final dose. In contrast, BMI and diabetes status influenced the final dose. Patient characteristics (BMI and diabetic status) may guide dosing of testosterone replacement with oral testosterone undecanoate to optimize T levels.

Chen X, Zhou B, Xie H, Guo X, Zhang J, Duncan JS, Miller EJ, Sinusas AJ, Onofrey JA, Liu C. DuSFE: Dual-Channel Squeeze-Fusion-Excitation co-attention for cross-modality registration of cardiac SPECT and CT. Med Image Anal. 2023 Aug;88:102840. doi: 10.1016/j.media.2023.102840. Epub 2023 May 16. PMID: 37216735.

Our studies using clinical patient MPI studies demonstrated that the DuSFE-embedded neural network generated significantly lower registration errors and more accurate AC SPECT images than existing methods. We also showed that the DuSFE-embedded network did not over-correct or degrade the registration performance of motion-free cases. The source code of this work is available at https://github.com/XiongchaoCh....

Van Batavia JP, Pohl HG, Farhat WA, Chiang G, BaniHani A, Collett-Gardere T, Franco I. Is it time to reconsider how we document pediatric uroflow studies?: A study from the SPU Voiding Dysfunction task force. J Pediatr Urol. 2023 May 12:S1477-5131(23)00147-X. doi: 10.1016/j.jpurol.2023.04.018. Epub ahead of print. PMID: 37302925.

For a more objective uroflow interpretation and comparison of studies among different centers, we recommend using our proposed system (based on FI, and smooth vs. fractionated curve pattern), which is more reliable.

Kucukkaya AS, Zeevi T, Chai NX, Raju R, Haider SP, Elbanan M, Petukhova-Greenstein A, Lin M, Onofrey J, Nowak M, Cooper K, Thomas E, Santana J, Gebauer B, Mulligan D, Staib L, Batra R, Chapiro J. Predicting tumor recurrence on baseline MR imaging in patients with early-stage hepatocellular carcinoma using deep machine learning. Sci Rep. 2023 May 10;13(1):7579. doi: 10.1038/s41598-023-34439-7. PMID: 37165035; PMCID: PMC10172370.

Our proof-of-concept study indicates that deep learning algorithms can be utilized to predict early-stage HCC recurrence. Successful identification of high-risk recurrence candidates may help optimize follow-up imaging and improve long-term outcomes post-treatment.

Smoyer AB, [Rickey L]. Negotiating toilet access: A qualitative exploration of women's incarceration. The Prison journal (Philadelphia, Pa.). 06/2023;103(3):329-346. doi: 10.1177/00328855231173146.

Norms and behaviors about toileting in prison can expand understanding of women's lived experience of incarceration. Knowledge about this subject is significant because access to clean, safe toilets is a human rights issue, and toilet habits can impact social, mental, and physical outcomes. Three focus groups were conducted with 15 incarcerated women about their quotidian prison toilet experiences. While the toilet was physically available, institutional regulations, social norms, and women's individual psychologies limited their access and utilization. The ways in which toilet use was negotiated with self, peers, and are described, and the implications of these findings are discussed.

Lokeshwar SD, Choksi AU, Haltstuch D, Rahman SN, Press BH, Syed J, Hurwitz ME, Kim IY, Leapman MS. Personalizing approaches to the management of metastatic hormone sensitive prostate cancer: role of advanced imaging, genetics and therapeutics. World J Urol. 2023 May 9. doi: 10.1007/s00345-023-04409-9. Epub ahead of print. PMID: 37160450.

Purpose: To summarize contemporary and emerging strategies for the diagnosis and management of metastatic hormone sensitive prostate cancer (mHSPC), focusing on diagnostic testing and therapeutics.

Chow RD, Long JB, Hassan S, Wheeler SB, Spees LP, Leapman MS, Hurwitz ME, McManus HD, Gross CP, Dinan MA. Disparities in immune and targeted therapy utilization for older US patients with metastatic renal cell carcinoma. JNCI Cancer Spectr. 2023 May 2;7(3):pkad036. doi: 10.1093/jncics/pkad036. PMID: 37202354; PMCID: PMC10276895.

Disparities in metastatic renal cell carcinoma (mRCC) outcomes persist in the era of oral anticancer agents (OAAs) and immunotherapies (IOs). We examined variation in the utilization of mRCC systemic therapies among US Medicare beneficiaries from 2015 to 2019. Logistic regression models evaluated the association between therapy receipt and demographic covariates including patient race, ethnicity, and sex. In total, 15 407 patients met study criteria.

Franco I, Coble J. Initial outcomes using a novel bedwetting alarm (Gogoband®) that utilizes real time artificial intelligence to wake users prior to wetting. J Pediatr Urol. 2023 Apr 29:S1477-5131(23)00153-5. doi: 10.1016/j.jpurol.2023.04.024. Epub ahead of print. PMID: 37217414.

We found 93% dry night rate in high compliance users in Weaning, this translates to 1.2 wet nights per 30 days. This compares to all users who wet 26.5 nights prior to treatment and 11.3 wet nights per 30 days during Training. The ability to achieve 14 days straight of dry nights was 85%. Our findings indicate that GOGOband® provides a significant benefit to all its users reducing nocturnal enuresis rates.

Arlen AM, Leong T, Kirsch AJ, Cooper CS. Spontaneous vesicoureteral reflux resolution curves based on ureteral diameter ratio. J Pediatr Urol. 2023 Aug;19(4):468.e1-468.e6. doi: 10.1016/j.jpurol.2023.04.028. Epub 2023 Apr 26. PMID: 37188603.

Children with primary VUR and a UDR of greater than 0.30 are significantly less likely to spontaneously resolve regardless of length of follow-up, and resolution after 3 years was rare. UDR provides objective prognostic information facilitating individualized patient management.

Chu CE, Leapman MS, Zhao S, Cowan JE, Washington SL, Cooperberg MR. Prostate cancer disparities among American Indians and Alaskan Natives in the United States. J Natl Cancer Inst. 2023 Apr 11;115(4):413-420. doi: 10.1093/jnci/djad002. PMID: 36629492; PMCID: PMC10086629.

American Indian or Alaska Native patients have more advanced prostate cancer, lower rates of definitive treatment, higher mortality, and reside in areas of less specialty care. Disparities in access appear to account for excess risks of PCSM. Focused health policy interventions are needed to address these disparities.

Zappia MP, Kwon YJ, Westacott A, Liseth I, Lee HM, Islam ABMMK, Kim J, Frolov MV. E2F regulation of the Phosphoglycerate kinase gene is functionally important in Drosophila development. Proc Natl Acad Sci U S A. 2023 Apr 11;120(15):e2220770120. doi: 10.1073/pnas.2220770120. Epub 2023 Apr 3. PMID: 37011211; PMCID: PMC10104548.

The canonical role of the transcription factor E2F is to control the expression of cell cycle genes by binding to the E2F sites in their promoters. However, the list of putative E2F target genes is extensive and includes many metabolic genes, yet the significance of E2F in controlling the expression of these genes remains largely unknown. Here, we used the CRISPR/Cas9 technology to introduce point mutations in the E2F sites upstream of five endogenous metabolic genes in Drosophila melanogaster. We found that the impact of these mutations on both the recruitment of E2F and the expression of the target genes varied, with the glycolytic gene, Phosphoglycerate kinase (Pgk), being mostly affected.

Franco I, Hoebeke PB, Dobremez E, Titanji W, Geib T, Jenkins B, Yushmanova I, Austin PF. Reply by Authors. J Urol. 2023 Apr;209(4):783-784. doi: 10.1097/JU.0000000000003157.03. Epub 2023 Apr 1. PMID: 36891836.

… can early intervention lead to the need for less medication and improved cognitive functioning in these children? Clearly there will be a need for an improved delivery system to avoid repeated anesthesia in young children …

Smani S, [Sprenkle P, Leapman, M]. MP75-01 ASSOCIATION BETWEEN SOCIODEMOGRAPHIC FACTORS AND DIAGNOSIS OF ADVANCED PROSTATE CANCER IN EARLY LIFE. The Journal of urology. 04/2023;209(supplement 4). doi: 10.1097/JU.0000000000003349.01.

A subset of patients are diagnosed with lethal prostate cancer early in life, before PSA screening is typically initiated. To identify opportunities for improved detection we evaluated patient clinical and sociodemographic factors associated with advanced versus localized prostate cancer diagnosis across the age spectrum.

Leapman M, [Martin D, Sprenkle P]. MP17-02 ASSOCIATION BETWEEN THE DECIPHER GENOMIC CLASSIFIER AND PROSTATE CANCER OUTCOME IN A LARGE-SCALE REAL-WORLD DATASET. The Journal of urology. 04/2023;209(supplement 4). doi: 10.1097/JU.0000000000003237.02.

Although the prognostic significance of the Decipher genomic classifier (GC) has been established in the context of randomized clinical trials and institutional cohorts, less is known about the associations between Decipher testing and oncologic outcomes among patients treated in the real-world practice setting.

Khan A, [Sprenkle P, Kellner D]. MP59-12 CAN ANATOMICAL MEASUREMENTS ON PREOPERATIVE PELVIC MAGNETIC RESONANCE IMAGING PREDICT POSTOPERATIVE URINARY INCONTINENCE AFTER HOLMIUM LASER ENUCLEATION OF THE PROSTATE? The Journal of urology. 04/2023;209(supplement 4). doi: 10.1097/JU.0000000000003312.12.

Preoperative measurement of IPPL is associated with postoperative urinary incontinence after HoLEP. Further anatomic features such as MUL, MUA, and LAT, which have been associated with incontinence after robotic prostatectomy, do not have an effect on postoperative incontinence after HoLEP in our study, suggesting such anatomical variations may play less of a role in postoperative incontinence. Further studies are needed to assess the impact of anatomical dimensions on surgical outcomes after HoLEP.

Leapman M, [Martin D, Sprenkle P]. MP17-09 DEVELOPMENT OF A LONGITUDINAL PROSTATE CANCER TRANSCRIPTOMIC AND REAL-WORLD CLINICAL DATA LINKAGE. The Journal of urology. 04/2023;209(supplement 4). doi: 10.1097/JU.0000000000003237.09.

We established the first national-scale linkage of transcriptomic and longitudinal clinical data yielding high accuracy for identifying key clinical junctures including diagnosis, treatment, and early cancer outcome. This resource can be leveraged to enhance understandings of disease biology, patterns of care and treatment effectiveness.

Sterling J. V09-04 REPAIR OF URINARY INCONTINENCE AND VENTRAL DEHISCENCE AFTER MASCULINIZING GENITAL GENDER AFFIRMATION SURGERY. The Journal of urology. 04/2023;209(supplement 4). doi: 10.1097/JU.0000000000003317.04.

Stress urinary incontinence (SUI) is an infrequently reported complication following transmasculine genital gender affirming surgery (gGAS), thus far there are no reports to help with management of severe SUI post gGAS. In this video, we demonstrate a case of de novo SUI following vaginectomy and metoidioplasty. These were treated with autologous fascial sling and staged urethral repair.

Lokeshwar S, [Singh D, Motamedinia P]. MP16-05 A NOVEL EMR-BASED CARE PATHWAY FOR NEPHROLITHIASIS: DEVELOPMENT AND 1 YEAR UTILIZATION. The Journal of urology. 04/2023;209(supplement 4). doi: 10.1097/JU.0000000000003236.05.

Patients with acute renal colic due to stones frequently visit the ED. With limited ED resources due to the COVID-19 pandemic, we developed a best practice management pathway within our electronic medical records (EMR) to provide consistent, expeditious and appropriate care for patients with nephrolithiasis. The objective of this study is to describe the development and 1 year outcomes of our EMR Care Pathway for nephrolithiasis.

Leapman M, [Sprenkle P]. PD10-01 ASSOCIATIONS BETWEEN PROSTATE MRI AND GENOMIC TESTING AND TREATMENT INTENSIFICATION AMONG PATIENTS WITH LOCALIZED PROSTATE CANCER. The Journal of urology. 04/2023;209(supplement 4). doi: 10.1097/JU.0000000000003250.01.

Prostate magnetic resonance imaging (MRI) and tissue-based gene expression (genomic) tests improve local staging and estimates of disease prognosis, however clinical management associated with their use in the real-world setting is not well understood.

Ocal S, [Franco I]. MP43-18 ADOLESCENT VARICOCELE: EFFECTS OF VEIN SIZE AND ARTERIAL FLOW RATE ON SEMINAL PARAMETERS. The Journal of urology. 04/2023;209(supplement 4). doi: 10.1097/JU.0000000000003289.18.

Varicocele severity has been associated with larger testicular vein size but the relationship to decreased fertility remains debatable. In clinical practice, largest vein diameter is used to screen for surgical intervention, yet more recent studies have found venous reflux patterns and total testicular volume (TTV) to be associated with total motile sperm count (TMSC). This study compares largest testicular vein size and arterial flow rates to identify patients at risk for reduced seminal parameters.

Esmaili R, [Leapman M, Sprenkle P, Martin D, Onofrey J]. PD38-08 AVOIDING UNNECESSARY TARGETED PROSTATE BIOPSIES USING MACHINE LEARNING. The Journal of urology. 04/2023;209(supplement 4). doi: 10.1097/JU.0000000000003336.08.

Our findings suggest that multivariate ML models using clinical data can be used to avoid unnecessary targeted biopsy cores among patients with suspicion of prostate cancer undergoing prostate biopsy.

Shain S, [Franco I]. MP70-01 MANAGEMENT OF THE REFRACTORY NOCTURNAL ENURESIS PATIENT TO DESMOPRESSIN IN A PEDIATRIC POPULATION: DESMOPRESSIN OXYBUTYNIN VS. DESMOPRESSIN IMIPRAMINE. The Journal of urology. 04/2023;209(supplement 4). doi: 10.1097/JU.0000000000003338.01.

Desmopressin (DDAVP) is well accepted as first-line medical therapy for nocturnal enuresis (NE). If DDAVP is ineffective, combination therapy of DDAVP+oxybutynin (Oxy) or DDAVP+imipramine (Imp) has been used. This study assessed the efficacy of adjunct therapy with either Imp or Oxy in the management of NE patients who failed DDAVP treatment.

Novosel M, [Sprenkle P, Leapman M]. PD20-07 ASSOCIATIONS BETWEEN PATIENT SOCIODEMOGRAPHIC FACTORS AND RISK-APPROPRIATE PROSTATE CANCER MANAGEMENT. The Journal of urology. 04/2023;209(supplement 4). doi: 10.1097/JU.0000000000003286.07.

Among patients diagnosed with prostate cancer in the contemporary era race and insurance are significantly associated with non-treatment for aggressive prostate cancer.

Leapman MS, Loeb S, Cooperberg MR, Catalona WJ, Gaylis FD. A vision for closing the evidence-practice gap in the management of low-grade prostate cancer. JNCI Cancer Spectr. 2023 Mar 1;7(2):pkad028. doi: 10.1093/jncics/pkad028. PMID: 37101361; PMCID: PMC10133397.

Gaps between clinical evidence and practice plague all domains of medicine. The time needed to translate the highest-quality evidence into clinical care is commonly estimated to be 17 years, an almost inconceivably slow pace (1,2). In this issue of the Journal, Borregales and colleagues (3) show that the conservative management of low-grade (ie, Gleason grade group 1) prostate cancer is no exception. Pathbreaking work over decades has chartered an evidentiary course supporting initial active surveillance as the preferred strategy for most men with low-grade prostate cancer (4,5). This approach has stood on solid ground for more than a decade and, in many instances, defers or avoids the possible adverse consequences of immediate treatment (6). Among patients with low-risk features—typically identified by the cancer grade, stage, and prostate-specific antigen (PSA) level—active surveillance is supported by level 1 evidence, a trove of high-quality prospective clinical and biological studies, and national guidelines. However, left to passive diffusion alone, active surveillance has been sluggish in uptake, highly varied in the quality of delivery, and often subject to premature termination (7).

SECONDARY FACULTY

Anderson KG, Braun DA, Buqué A, Gitto SB, Guerriero JL, Horton B, Keenan BP, Kim TS, Overacre-Delgoffe A, Ruella M, Triplett TA, Veeranki O, Verma V, Zhang F. Leveraging immune resistance archetypes in solid cancer to inform next-generation anticancer therapies. J Immunother Cancer. 2023 Jun;11(6):e006533. doi: 10.1136/jitc-2022-006533. PMID: 37399356; PMCID: PMC10314654.

We propose that cancers can be characterized by immune resistance archetypes, comprised of five feature sets encompassing known immune resistance mechanisms. Archetypes of resistance may inform new therapeutic strategies that concurrently address multiple cell axes and/or suppressive mechanisms, and clinicians may consequently be able to prioritize targeted therapy combinations for individual patients to improve overall efficacy and outcomes.

Saad E, Saliby RM, Labaki C, Xu W, Viswanathan SR, Braun DA, Bakouny Z. Novel Immune Therapies for Renal Cell Carcinoma: Looking Beyond the Programmed Cell Death Protein 1 and Cytotoxic T-Lymphocyte-Associated Protein 4 Axes. Hematol Oncol Clin North Am. 2023 Jun 28:S0889-8588(23)00078-3. doi: 10.1016/j.hoc.2023.05.023. Epub ahead of print. PMID: 37391289.

Immunotherapy has revolutionized treatment for patients with advanced and metastatic renal cell carcinoma. Nevertheless, many patients do not benefit or eventually relapse, highlighting the need for novel immune targets to overcome primary and acquired resistance. This review discusses 2 strategies currently being investigated: disabling inhibitory stimuli that maintain immunosuppression ("brakes") and priming the immune system to target tumoral cells ("gas pedals"). We explore each class of novel immunotherapy, including the rationale behind it, supporting preclinical and clinical evidence, and limitations.

O'Donnell PH, Milowsky MI, Petrylak DP, Hoimes CJ, Flaig TW, Mar N, Moon HH, Friedlander TW, McKay RR, Bilen MA, Srinivas S, Burgess EF, Ramamurthy C, George S, Geynisman DM, Bracarda S, Borchiellini D, Geoffrois L, Maroto Rey JP, Ferrario C, Carret AS, Yu Y, Guseva M, Homet Moreno B, Rosenberg JE. Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. J Clin Oncol. 2023 Jun 27:JCO2202887. doi: 10.1200/JCO.22.02887. Epub ahead of print. PMID: 37369081.

Patients with locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible for cisplatin-based therapy have limited first-line (1L) treatment options and significant need for improved therapies. Enfortumab vedotin (EV) and pembrolizumab (Pembro) individually have shown a survival benefit in urothelial cancer in second-line + la/mUC settings. Here, we present data from the pivotal trial of EV plus Pembro (EV + Pembro) in the 1L setting.

Saliby RM, Saad E, Labaki C, Xu W, Braun DA, Viswanathan SR, Bakouny Z. Novel Targeted Therapies for Renal Cell Carcinoma: Building on the Successes of Vascular Endothelial Growth Factor and mTOR Inhibition. Hematol Oncol Clin North Am. 2023 Jun 27:S0889-8588(23)00077-1. doi: 10.1016/j.hoc.2023.05.022. Epub ahead of print. PMID: 37385938.

Targeted therapies have revolutionized the treatment of renal cell carcinoma (RCC). The VHL/HIF pathway is responsible for the regulation of oxygen homeostasis and is frequently altered in RCC. Targeting this pathway as well as the mTOR pathway have yielded remarkable advances in the treatment of RCC. Here, we review the most promising novel targeted therapies for the treatment of RCC, including HIF2α, MET, metabolic targeting, and epigenomic reprogramming.

Sun G, Dizon DS, Szczepanek CM, Petrylak DP, Sparks DB, Tangen C, Lara PLN Jr, Thompson IM Jr, Blanke CD. Crisis of the Clinical Trials Staff Attrition After the COVID-19 Pandemic. JCO Oncol Pract. 2023 Jun 7:OP2300152. doi: 10.1200/OP.23.00152. Epub ahead of print. PMID: 37285550.

A survey of clinical research professionals @SWOG indicate that 80% of clinical trial offices are understaffed. Addressing this is critical so progress for people with cancer continues. Read more about lessons learned in the #COVID19 pandemic and how it informs a path forward.

Saliby RM, El Zarif T, Bakouny Z, Shah V, Xie W, Flippot R, Denize T, Kane MH, Madsen KN, Ficial M, Hirsch L, Wei XX, Steinarter JA, Harshman LC, Vaishampayan UN, Severgnini M, McDermott DF, Lee GM, Xu W, Van Allen EM, McGregor BA, Signoretti S, Choueiri TK, McKay RR, Braun DA. Circulating and intratumoral immune determinants of response to atezolizumab plus bevacizumab in patients with variant histology or sarcomatoid renal cell carcinoma. Cancer Immunol Res. 2023 Jun 6:CIR-22-0996. doi: 10.1158/2326-6066.CIR-22-0996. Epub ahead of print. PMID: 37279009.

Overall, these findings support the value of tumor and blood-based immune assessments in determining therapeutic benefit for patients with RCC receiving atezolizumab plus bevacizumab and provide a foundation for future biomarker studies for patients with variant histology RCC receiving immunotherapy-based combinations.

Sadeghi S, [Petrylak D]. A phase III randomized trial of eribulin (E) with or without gemcitabine vs standard of care (SOC) for metastatic urothelial carcinoma (UC) refractory to or ineligible for PD/PDL1 antibody (ab): SWOG S1937. Journal of clinical oncology. 06/2023;41(16_suppl):TPS4608-TPS4608. doi: 10.1200/JCO.2023.41.16_suppl.TPS4608.

This is a phase III, randomized 3 arm study comparing E vs. GE vs. SOC (docetaxel, paclitaxel, or gemcitabine)… The study was activated in Feb 2021 and accrual is ongoing. Clinical trial information: NCT04579224.

El Ahmar N, [Braun D]. Biomarkers of response to first-line nivolumab therapy in patients with advanced renal cell carcinoma (RCC) enrolled in the HCRN GU16-260 trial. Journal of clinical oncology. 06/2023;41(16_suppl):4549-4549. doi: 10.1200/JCO.2023.41.16_suppl.4549.

High levels of CD8+ PD1+ TIM-3-LAG-3- TILs were associated with response to first-line nivo in pts with advanced RCC and the combination with TC PD-L1 status further separated the outcomes of pts with ccRCC, validating our previous findings. Further investigations into the role of myeloid inflammation as determinant of clinical outcome to nivo therapy are ongoing. Clinical trial information: NCT03117309.

Gupta S, [Petrylak, D]. Study EV-103 dose escalation/cohort A: Long-term outcome of enfortumab vedotin pembrolizumab in first-line (1L) cisplatin-ineligible locally advanced or metastatic urothelial carcinoma (la/mUC) with nearly 4 years of follow-up. Journal of clinical oncology. 06/2023;41(16_suppl):4505-4505. doi: 10.1200/JCO.2023.41.16_suppl.4505.

EV+P, continues to demonstrate promising survival trends with rapid and durable responses in 1L cisplatin-ineligible pts with la/mUC. The safety profile of the combination is manageable and stable with a longer follow-up, and no new safety concerns have emerged. These results are concordant with previously reported DE/A data by investigator assessment and support the evaluation of EV+P in ongoing phase 3 studies in UC. Clinical trial information: NCT03288545.

McGregor BA, [Braun D]. Phase II study of cabozantinib (cabo) with nivolumab (nivo) and ipilimumab (ipi) in advanced renal cell carcinoma with variant histologies (RCCvh). Journal of clinical oncology. 06/2023;41(16_suppl):4520-4520. doi: 10.1200/JCO.2023.41.16_suppl.4520.

At this time combinations of immunotherapy and targeted therapy yield response rates near 50% in patients with RCCvh, but novel approaches are still needed. The authors of this trial expanded the treatment paradigm of the Cosmic-313 study to patients with variant Histology RCC.

Aggarwal RR, [Petrylak D]. First-in-class oral innate immune activator BXCL701 combined with pembrolizumab, in patients with metastatic castration-resistant prostate cancer (mCRPC) of small cell neuroendocrine (SCNC) variant: Randomized phase 2b trial. Journal of clinical oncology. 06/2023;41(16_suppl):TPS5109-TPS5109. doi: 10.1200/JCO.2023.41.16_suppl.TPS5109.

No evidence found that BXCL701 potentiates immune-related AEs related to immune checkpoint inhibitors. DPP9 overexpression was identified as a potential predictive biomarker for BXCL701 response; biomarker evaluation is ongoing and additional findings will be presented at an upcoming medical meeting. Since SCNC cohort showed encouraging efficacy in Phase 2a, the Phase 2b portion of study was initiated to evaluate SCNC variant in a potential registrational randomized study.

Saliby RM, [Braun D]. Immune landscape of patients with metastatic non-clear cell renal cell carcinoma (nccRCC) treated with atezolizumab plus bevacizumab. Journal of clinical oncology. 06/2023;41(16_suppl):4535-4535. doi: 10.1200/JCO.2023.41.16_suppl.4535.

Among patients with advanced nccRCC or sccRCC, a baseline high systemic inflammatory state and high circulating VEGF-A are associated with worse outcomes after treatment with atezolizumab and bevacizumab. High levels of intratumor terminally exhausted CD8+ T cells were associated with worse PFS.

Friedlander TW, [Petrylak D]. Enfortumab vedotin (EV) with or without pembrolizumab (P) in patients (pts) who are cisplatin-ineligible with previously untreated locally advanced or metastatic urothelial cancer (la/mUC): Additional 3-month follow-up on cohort K data. Journal of clinical oncology. 06/2023;41(16_suppl):4568-4568. doi: 10.1200/JCO.2023.41.16_suppl.4568.

With an additional 3 months of follow-up, EV+P continues to show a high cORR with rapid and durable responses as 1L treatment in cisplatin-ineligible pts with la/mUC, including a manageable safety profile with no new safety concerns after extended treatment exposure. DOR, PFS and OS will evolve with further follow-up and continue to trend similarly to those of DE/A; EV monotherapy was consistent with prior results. Clinical trial information: NCT03288545.

Labaki C, [Braun D]. Efficacy of first-line (1L) immunotherapy (IO)-based regimens in patients with sarcomatoid and/or rhabdoid (S/R) metastatic non-clear cell renal cell carcinoma (nccRCC): Results from the international metastatic renal cell carcinoma database consortium (IMDC). Journal of clinical oncology. 06/2023;41(16_suppl):4519-4519. doi: 10.1200/JCO.2023.41.16_suppl.4519.

To our knowledge, this represents the largest effort to characterize the outcomes of patients with S/R nccRCC treated with IO regimens. Patients with S/R nccRCC appear to derive a substantial and selective benefit from IO regimens (vs. VEGF-TT). These data support the use of IO-based regimens in patients with S/R nccRCC.

Loriot Y., [Petrylak, D]. Efficacy of sacituzumab govitecan (SG) in locally advanced (LA) or metastatic urothelial cancer (mUC) by trophoblast cell surface antigen 2 (trop-2) expression. Journal of clinical oncology. 06/2023;41(16_suppl):4579-4579. doi: 10.1200/JCO.2023.41.16_suppl.4579.

In this analysis of archival tumor samples from pts with pretreated LA or mUC, Trop-2 protein was highly expressed across cohorts, supporting prior Trop-2 expression analyses in UC. Similar outcomes were observed between C1 pts with samples that were below and above median Trop-2 H-score with most pronounced numerical differences observed for PFS. These results suggest that SG activity may be independent of Trop-2 expression in UC, but additional studies are needed to confirm these results. Clinical trial information: NCT03547973.

Flaig TW, [Petrylak DP]. Study EV-103: Neoadjuvant treatment with enfortumab vedotin monotherapy in cisplatin-ineligible patients (pts) with muscle invasive bladder cancer (MIBC): Updated results for cohort H. Journal of clinical oncology. 06/2023;41(16_suppl):4595-4595. doi: 10.1200/JCO.2023.41.16_suppl.4595.

Neoadjuvant EV monotherapy treatment showed promising results for antitumor activity and EFS with a manageable safety profile in cisplatin-ineligible pts with MIBC. These results support ongoing phase 2 and 3 programs in MIBC evaluating EV alone or combined with pembrolizumab (EV-103 Cohort L, KN-905, KN-B15). Clinical trial information: NCT03288545.

Braun DA, [Hurwitz, M]. Determinants of resistance to nivolumab (nivo) monotherapy investigated through genomic and transcriptomic analysis of renal cell carcinoma (RCC) tumors from the HCRN GU16-260 study. Journal of clinical oncology. 06/2023;41(16_suppl):4524-4524. doi: 10.1200/JCO.2023.41.16_suppl.4524.

Bulk genomic and single-cell transcriptomic analyses uncovered somatic alterations (amp11q13) and infiltrating T cell populations (SLAMF7+ CD8+) associated with resistance to frontline nivo monotherapy in a phase II study in RCC. Additional independent and functional validation studies are in progress.

Saad E, [Braun D]. Association of host immune signatures with response to immunotherapy-based regimens in patients with metastatic renal cell carcinoma (mRCC). Journal of clinical oncology. 06/2023;41(16_suppl):4550-4550. doi: 10.1200/JCO.2023.41.16_suppl.4550.

We were successfully able to characterize T-cell receptor and IgH repertoires in a large cohort of patients with mRCC and evaluate their associations with ICI response. Our results show that baseline TCR clonality and IgG1 antibody fraction are associated with the response to ICI regimens, suggesting a potential role for immune biomarker development.

Labaki C, [Braun D]. Characterization of the immunophenotype and tumor specificity of CD8 T-cells in chromophobe renal cell carcinoma (ChRCC) and renal oncocytic neoplasms. Journal of clinical oncology. 06/2023;41(16_suppl):4558-4558. doi: 10.1200/JCO.2023.41.16_suppl.4558.

In ChRCC, there is low infiltration by CD45+ immune cells. Although infiltrating CD8+ T cells have a predominantly non-exhausted immune phenotype, they likely lack anti-tumor specificity (i.e. are “bystander” T cells). These findings may help to understand the molecular basis for the lack of response to immunotherapy recently identified among patients with advanced ChRCC, and support future therapeutic strategies to increase infiltration of tumor-specific T cells into the tumor microenvironment.

Loriot Y, [Petrylak DP]. Safety analysis by UGT1A1 status of TROPHY-U-01 cohort 1, a phase 2 study of sacituzumab govitecan (SG) in patients (pts) with metastatic urothelial cancer (mUC) who progressed after platinum (PT)-based chemotherapy and a checkpoint inhibitor (CPI). Journal of clinical oncology. 06/2023;41(16_suppl):4514-4514. doi: 10.1200/JCO.2023.41.16_suppl.4514.

With longer follow-up, SG safety profile was consistent with prior reports. The incidence of adverse events varied across UGT1A1 subgroups, with dose interruptions being more frequently observed in homozygous pts. This was an exploratory analysis with relativity low numbers in each subgroup. Additional studies are needed to confirm the impact of UGT1A1 status on safety outcomes with SG in UC. Clinical trial information: NCT03547973.

Braun DA, Chakraborty AA. Immunobiology and Metabolic Pathways of Renal Cell Carcinoma. Hematol Oncol Clin North Am. 2023 May 26:S0889-8588(23)00046-1. doi: 10.1016/j.hoc.2023.04.012. Epub ahead of print. PMID: 37246090.

The treatment of advanced renal cell carcinoma (RCC) has changed dramatically with immune checkpoint inhibitors, yet most patients do not have durable responses. There is consequently a tremendous need for novel therapeutic development. RCC, and particularly the most common histology clear cell RCC, is an immunobiologically and metabolically distinct tumor. An improved understanding of RCC-specific biology will be necessary for the successful identification of new treatment targets for this disease. In this review, we discuss the current understanding of RCC immune pathways and metabolic dysregulation, with a focus on topics important for future clinical development.

Armstrong AJ, Iguchi T, Azad AA, Villers A, Alekseev B, Petrylak DP, Szmulewitz RZ, Alcaraz A, Shore ND, Holzbeierlein J, Gomez-Veiga F, Rosbrook B, Zohren F, Haas GP, Gourgiotti G, El-Chaar N, Stenzl A. The Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Oligometastatic Hormone-sensitive Prostate Cancer: A Post Hoc Analysis of ARCHES. Eur Urol. 2023 Aug;84(2):229-241. doi: 10.1016/j.eururo.2023.04.002. Epub 2023 May 12. PMID: 37179240.

This study considered two treatment options for metastatic hormone-sensitive prostate cancer in patients with one to five metastases or six or more metastases. Treatment with enzalutamide plus ADT improved survival and other outcomes over ADT alone, whether patients had few or many metastases.

Lokeshwar SD, Choksi AU, Haltstuch D, Rahman SN, Press BH, Syed J, Hurwitz ME, Kim IY, Leapman MS. Personalizing approaches to the management of metastatic hormone sensitive prostate cancer: role of advanced imaging, genetics and therapeutics. World J Urol. 2023 May 9. doi: 10.1007/s00345-023-04409-9. Epub ahead of print. PMID: 37160450.

Purpose: To summarize contemporary and emerging strategies for the diagnosis and management of metastatic hormone sensitive prostate cancer (mHSPC), focusing on diagnostic testing and therapeutics.

Chow RD, Long JB, Hassan S, Wheeler SB, Spees LP, Leapman MS, Hurwitz ME, McManus HD, Gross CP, Dinan MA. Disparities in immune and targeted therapy utilization for older US patients with metastatic renal cell carcinoma. JNCI Cancer Spectr. 2023 May 2;7(3):pkad036. doi: 10.1093/jncics/pkad036. PMID: 37202354; PMCID: PMC10276895.

Grivas P, Park SH, Voog E, Caserta C, Gurney H, Bellmunt J, Kalofonos H, Ullén A, Loriot Y, Sridhar SS, Yamamoto Y, Petrylak DP, Sternberg CN, Gupta S, Huang B, Costa N, Laliberte RJ, di Pietro A, Valderrama BP, Powles T. Avelumab First-line Maintenance Therapy for Advanced Urothelial Carcinoma: Comprehensive Clinical Subgroup Analyses from the JAVELIN Bladder 100 Phase 3 Trial. Eur Urol. 2023 Jul;84(1):95-108. doi: 10.1016/j.eururo.2023.03.030. Epub 2023 Apr 28. PMID: 37121850.

Analyses of OS and PFS in clinically relevant subgroups were consistent with results for the overall population, further supporting avelumab 1L maintenance as standard-of-care treatment for patients with aUC who are progression-free following 1L platinum-based chemotherapy.

Lu YT, Plets M, Morrison G, Cunha AT, Cen SY, Rhie SK, Siegmund KD, Daneshmand S, Quinn DI, Meeks JJ, Lerner SP, Petrylak DP, McConkey D, Flaig TW, Thompson IM Jr, Goldkorn A. Cell-free DNA Methylation as a Predictive Biomarker of Response to Neoadjuvant Chemotherapy for Patients with Muscle-invasive Bladder Cancer in SWOG S1314. Eur Urol Oncol. 2023 Apr 20:S2588-9311(23)00074-3. doi: 10.1016/j.euo.2023.03.008. Epub ahead of print. PMID: 37087309.

In this exploratory analysis of S1314, we demonstrated that cell-free DNA methylation can be profiled to generate biomarker signatures associated with neoadjuvant chemotherapy response. With validation in additional cohorts, this minimally invasive approach may be used to predict chemotherapy response in locally advanced bladder cancer and perhaps also in metastatic disease.

Antonarakis ES, Subudhi SK, Pieczonka CM, Karsh LI, Quinn DI, Hafron JM, Wilfehrt HM, Harmon M, Sheikh NA, Shore ND, Petrylak DP. Combination Treatment with Sipuleucel-T and Abiraterone Acetate or Enzalutamide for Metastatic Castration-Resistant Prostate Cancer: STAMP and STRIDE Trials. Clin Cancer Res. 2023 Jul 5;29(13):2426-2434. doi: 10.1158/1078-0432.CCR-22-3832. PMID: 37058234; PMCID: PMC10320463.

Median OS was consistent regardless of whether the agents were administered sequentially or concurrently, including after NDI update. Results suggest that sipuleucel-T induces an immunologic prime-boost effect after initial sipuleucel-T exposure, even when combined with ARTAs.

Halabi S, Yang Q, Roy A, Luo B, Araujo JC, Logothetis C, Sternberg CN, Armstrong AJ, Carducci MA, Chi KN, de Bono JS, Petrylak DP, Fizazi K, Higano CS, Morris MJ, Rathkopf DE, Saad F, Ryan CJ, Small EJ, Kelly WK. External Validation of a Prognostic Model of Overall Survival in Men With Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. 2023 May 20;41(15):2736-2746. doi: 10.1200/JCO.22.02661. Epub 2023 Apr 11. PMID: 37040594.

This prognostic model for OS in docetaxel-naïve men with mCRPC has been validated using data from seven trials and yields similar results overall and across race, age, and different treatment classes. The prognostic risk groups are robust and can be used to identify groups of patients for enrichment designs and for stratification in randomized clinical trials.

Djureinovic D, [Hurwitz M]. Abstract 3287: A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better. Cancer research (Chicago, Ill.). 04/2023;83(7_supplement):3287-3287. doi: 10.1158/1538-7445.AM2023-3287.

Our study suggests that more anti-CSF1R might not be better. Further optimization of cabiralizumab dosing is necessary to evaluate the clinical potential in combination with anti-PD-1 and anti-CD40 in a difficult-to treat patient population whose therapeutic options are limited.

Yale Urology Research [Q2: April-June 2023]

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