A recent study published in Urology described how American Urological Association–accredited urological residency training programs are organized in terms of clinical exposure and teaching of their residents.

First study portrays urology resident clinical experience in the United States

Investigators have discovered that the loss of the gene 

 in circulating tumor cells regulates metastasis of prostate cancer tumors, according to a Northwestern Medicine study 

Metastasis accounts for most cancer-related deaths, yet its underlying mechanisms have remained poorly understood despite recent advances in cancer treatments and care.

Circulating tumor cells (CTCs) drive cancer metastasis by breaking off from primary tumors and traveling through the bloodstream to seed new tumors. However, identifying the genetic factors that regulate CTCs and help them enter the bloodstream has remained a major roadblock due to CTCs’ rarity and heterogeneous nature.

“If we could turn off metastasis, cancer would not be deadly. Understanding why CTCs enter the blood is a critical step,” said Shana Kelley, PhD, professor of Biochemistry and Molecular Genetics, the Neena B. Schwartz Professor of Chemistry and Biomedical Engineering at the McCormick School of Engineering and senior author of the study.

To uncover the mechanisms driving CTC migration, the investigators usedCRISPR gene editing to knock out genes in tumor-forming prostate cancer cells implanted in mice, with each cell having loss of function of one gene in the human genome. CTCs were collected using a first-of-its-kind approach developed by Kelley’s laboratory that efficiently isolates CTCs from blood cells.

From this screening, the investigators identified 

 as the most common gene associated with CTCs. The gene encodes the SLIT2 protein, which in turn influences cellular migration. When 

 knockout CTCs were inserted back into the mouse model, the investigators found that the number of CTCs increased in the bloodstream of mice.

 loss in circulating tumor cells promotes metastasis and enhances cancer progression. According to Kelley, next steps will involve screening genes that are activated, rather than knocked out, to identify new drug targets that could potentially slow or prevent metastasis.

“We know that in patients if there’s a loss of 

, there are poorer outcomes, so this suggests that if we could bring back 

 function we could keep metastasis from happening,” said Kelley, who is a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

This work was supported by the Canadian Institutes of Health Research grant FDN-148415.

Articles

Research findings suggest that SLIT2 loss in circulating tumor cells promotes metastasis and enhances cancer progression, according to a Northwestern Medicine study published in Science Advances.

Gene loss enhances prostate cancer progression and metastasis 

® is celebrating its 50th anniversary in 2022. To mark the occasion, we are highlighting 50 of the top innovations and developments that have transformed the field of urology over the past 50 years. In this installment, 

, discusses the use of multiparametric MRI (mpMRI) in prostate cancer. Parker is a practicing urologist at The University of Kanas Health System and an assistant professor at the University of Kansas Medical Center.

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“From a screening perspective, mpMRI really has changed how we evaluate men at risk for prostate cancer. It has improved the selection of men for biopsy and certainly improved our diagnostic rates,” says William P. Parker, MD.

Urology Times 50 Innovations Series: Multiparametric MRI in prostate cancer

Health care providers can probably work effectively with most types of medical software; however, the financial resources they are able to invest in medical solutions differ significantly based on the type of practice.

Although there are numerous classifications of health care providers, this article categorizes providers based on their current life cycle stage. According to this classification, medical providers fall into three groups: 

Health care providers are business entities, so their life cycle, like that of any business, consists of the early stage or launch, growth and maturity. At each stage, providers have different priorities and goals, and the choice of medical software solutions should be made accordingly.

The launch phase can be tough. At this stage, the profits are usually low and providers may even incur losses. Hence, they need tools that enable efficient work at this point, such as an electronic health records (EHR) solution, a patient scheduling tool and billing software. Those tools can make a solid foundation for any clinical operation.

An EHR stores patient health data, including medical histories, lab data, and more. This information is paramount for accurate diagnostics. Scheduling solutions allow providers to coordinate patients’ appointments with clinicians’ schedules and the available rooms, thus preventing confusion and ensuring timeand cost efficiency. Billing software automates billing and filing insurance claims and helps manage them. Such software also can inform users about upcoming deadlines on document submission or payments.

At the stage when the profits are stable, providers aim at increasing their customer base. This is when mobile technologies may be of help. As of 2021, 85% of the U.S. population own a smartphone. This means medical providers can consider integrating some engaging mobile apps in their practice. The experts recommend starting with a mobile-friendly patient portal, as it allows providers to build strong relationships with their patients.

Using the portal, a patient can view, download, and send their health information to providers. They also can suggest edits to their treatment and medication plans, which improves their adherence. Although patients manage their health independently, doctors can supervise.

Experts recommend setting up a telemedicine solution after launching a portal. Telemedicine tools helped medical providers during the COVID-19 pandemic offer an opportunity to deliver care without virus exposure. Though the crisis is subsiding, telemedicine tools remain relevant. They can be valid solutions for nonurgent care provision for busy professionals, chronic-condition patients, and patients in remote or rural locations.

Medical software for well-established providers

At the final stage, all clinical processes are up and running. However, their course is not always smooth and trouble-free, so there is a need for process optimization. Direct messaging solutions and speech recognition software can speed up clinical processes and even reduce clinicians’ burnout rate. According to results of a recent physicians poll by Medical Economics®, approximately 80% of respondents are dealing with burnout. Curiously, it’s not the pandemic that is to blame here. Instead, the respondents said, burnout was caused by the complexity of administrative tasks. So how can technology help?

Direct messaging solutions ensure secure health data transmission across a private network run by a Health Information Service Provider. Health care providers use direct secure messaging to send referrals, transfer patient care plans, and communicate with patients. Such tools are compliant with the Health Insurance Portability and Accountability Act and support confidentiality of patient-doctor communication. Those tools save clinicians a lot of time and effort in ensuring secure data sharing.

Speech recognition software, the tools transform speech into text, allows clinicians to save time on tasks such as taking patient notes.

Well-informed decision-making is often the key success factor in health care, and analytics solutions can bring this process to a new level. Although many tools are optional for beginners, they can be a game changer for well-established providers.

Inga Shugalo is a health care industry analyst with Itransition. Send your technology questions to medec@mjhlifesciences.com.

At each stage, health care providers have different priorities and goals, and the choice of medical software solutions should be made accordingly.

Medical software should be chosen based on your practice’s life cycle stage

, hematologist/oncologist, Kaiser Permanente Riverside Medical Center, discusses the current state of the prostate cancer paradigm as well as unmet needs in the space.

Helen Heng-Shan Moon, MD, reflects on major advances in prostate cancer over the past 10 years and unmet needs that remain.

Dr. Moon on latest progress and unmet needs in prostate cancer care

The accuracy of biopsy sampling, which can miss clinically significant tumors, limits our ability to detect prostate cancer extent and aggressiveness. MRI-guided ultrasound fusion biopsies can improve accuracy, but often the standard-of-care MR images can miss some tumors and are not reliable for determining aggressiveness. Investigators from the Hyperpolarized MRI Technology Resource Center (HMTRC) at UCSF set out to study whether hyperpolarized (HP) pyruvate MRI can a) detect cancer based on its metabolic reprogramming and b) whether it can assess tumor aggressiveness.

Our recent publication describes the first project to utilize HP pyruvate MRI in combination with anatomic and diffusion MRI to benefit biopsy guidance for prostate cancer patients,” says radiologist Z. Jane Wang, MD, medical director of the HMTRC. Findings from this proof-of-concept work were recently published in 

 

“The first in human trial of hyperpolarized (HP) carbon-13 (

C) MRI at UCSF published in 2013 showed not only the safety of the technique but also detected a region of prostate cancer that was not seen on anatomic or diffusion MR imaging,” says Daniel Vigneron, PhD, director of the UCSF HMTRC and corresponding author on this study.

"HP 

C MRI provides a quick five-minute, non-radioactive, metabolic imaging add-on exam to standard-of-care MRI that, in conjunction with guided biopsies, has great potential to improve the care of prostate cancer patients,” says Robert Bok, MD, PhD, professor in the Department of Radiology & Biomedical Imaging and the HMTRC. “The rapid assessment of the presence and aggressiveness of a patient’s cancer has the potential to provide patients with an individualized approach to cancer treatment,” adds Michael Ohliger, MD, PhD, an associate professor in Radiology & Biomedical Imaging and HMTRC member.


The full team of investigators include Hsin-Yu Chen, PhD, Lucas Carvajal, MS, and Daniel Gebrezgiabhier, from the UCSF HMTRC; Dr. Robert Bok, Jeremy Gordon, PhD, John Kurhanewicz, PhD, Peder Larson, PhD, Dr. Michael Ohliger, Daniel Vigneron, PhD, Dr. Z. Jane Wang, UCSF Radiology & Biomedical Imaging and HMTRC faculty; Rahul Aggarwal, MD, from UCSF Hematology/Oncology; Matthew R. Cooperberg, MD, MPH, Hao Nguyen, MD, PhD, and Katsuto Shinohara, MD, from UCSF Urology and Antonio Westphalen, MD, PhD, from the University of Washington, Department of Radiology.

The goal of the HMTRC is to collaboratively develop new technology to advance this field in order to better identify and understand human disease and ultimately to translate and disseminate these techniques for improved healthcare. Visit our website to learn more about HP MRI resources and Technology Research & Development Projects.

"HP 13C MRI provides a quick five-minute, non-radioactive, metabolic imaging add-on exam to standard-of-care MRI that, in conjunction with guided biopsies, has great potential to improve the care of prostate cancer patients,” said Robert Bok, MD, PhD.

UCSF investigators improve MR-guided TRUS fusion biopsy for prostate cancer detection using HP 13C MRI

Adding the PARP inhibitor talazoparib (Talzenna) to enzalutamide (Xtandi) improved radiographic progression-free survival (rPFS) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC), regardless of homologous recombination repair (

) gene mutation status, according to topline results from the phase 3 TALAPRO-2 trial.

The study met its primary endpoint, as the hazard ratio for rPFS exceeded the pre-specified threshold of 0.696, meaning the combination reduced the risk of disease progression or death by at least 30.4% versus enzalutamide alone.

The talazoparib/enzalutamide combination was also shown to have benefits in key secondary end points, including prostate specific antigen (PSA) response, time to PSA progression, and overall response rate (ORR). Although overall survival (OS) data from TALAPRO-2 trial remain immature, there was a trend toward an OS improvement with the combination observed at the time of the analysis.

Overall the 2-part, 2-cohort, multicenter, double-blind TALAPRO-2 trial (NCT03395197) enrolled 1095 patients with systemic therapy­–naïve mCRPC at clinical sites in the United States, Canada, Europe, South America, and the Asia-Pacific region. The study included an all-comer cohort of 750 patients and a 

 mutation–positive cohort of 380 patients. Patients were randomized to enzalutamide at 160 mg/day plus either talazoparib at 0.5 mg/day or placebo.

 mutation–positive cohort. At the time of the analysis, there were no new safety signals with talazoparib or enzalutamide compared with those previously reported.

Pfizer, which develops both study treatments, reported in a press release that it intends to submit the TALAPRO-2 findings for presentation at an upcoming medical meeting.

“Xtandi is a global standard of care, with overall survival demonstrated in mCRPC, non-metastatic CRPC, and metastatic castration-sensitive prostate cancer (mCSPC),” Chris Boshoff, MD, PhD, chief development officer, Oncology and Rare Disease, Pfizer Global Product Development, stated in the press release. “We are very pleased with the strong findings from TALAPRO-2, and although no definitive conclusions can be made across trials, the rPFS appears to be the longest observed in a randomized trial in this setting. These data highlight the potential for Talzenna in combination with Xtandi, if approved, to become a new standard of care for mCRPC, irrespective of 

 gene mutation status. We look forward to discussing these data with global health authorities.”

Previously reported data from the phase 2 TALAPRO-1 trial showed antitumor activity with single-agent in patients with heavily pretreated mCRPC that harbored DNA damage response 

In the study, patients received at least 1 dose of 1 mg daily of oral talazoparib at 43 medical facilities around the globe. Patients were previously treated with at least 1 taxane-based chemotherapy, as well as abiraterone acetate (Zytiga)/prednisone, enzalutamide, or both hormonal agents.

All patients had at least 1 HHR gene alteration from a panel of 11 genes likely to sensitize their tumor to PARP inhibition: 

ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C

At a median follow-up of 16.4 months (interquartile range, 11.1-22.1), the ORR was 29.8% (95% CI, 21.2%-39.6%) among 104 evaluable patients. Antitumor effects were most notable in patients with BRCA1/2 mutations, with a confirmed ORR of 45.9% and a median rPFS of 11.2 months.

In the safety analysis of 127 patients, the most common grade 3/4 treatment-emergent adverse events (TEAEs) were anemia (31%), thrombocytopenia (9%), and neutropenia (8%). Investigators observed serious TEAEs in 34% of patients. There were no treatment-related deaths.

Other study from the TALAPRO program,the 

 (NCT04821622), is evaluating the combination of talazoparib and enzalutamide in patients with 

1. Pfizer Announces Positive Topline Results from Phase 3 TALAPRO-2 Trial. Published online and accessed October 4, 2022. https://bit.ly/3SQBHn2

2. de Bono JS, Mehra N, Scagliotti GV, et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021;22(9):1250-1264. doi:10.1016/S1470-2045(21)00376-4

The talazoparib/enzalutamide combination was also shown to have benefits in key secondary end points, including prostate specific antigen (PSA) response, time to PSA progression, and overall response rate.

Talazoparib/enzalutamide improves rPFS in mCRPC, regardless of HRR gene mutation status

The PARP inhibitor rucaparib (Rubraca) improved radiographic progression-free survival (rPFS) versus chemotherapy or second-line androgen deprivation therapy (ADT) in patients with metastatic castration-resistant prostate cancer (mCRPC) that harbored a deleterious 

 mutation, according to topline findings from the phase 3 TRITON3 trial.

Independent radiology review (IRR) determined that in the overall intent-to-treat (ITT) population of patients with a 

 mutation, rucaparib led to a 3.8-month improvement in median rPFS versus the control arm of chemotherapy or second-line ADT, translating to a 39% reduction in the risk of disease progression or death. The rucaparib benefit was even more pronounced in the subgroup of patients with a 

 mutation. In these patients, the median rPFS benefit for the PARP inhibitor vs the control arm was 4.8 months, translating to a 50% reduction in the risk of disease progression or death.

“Men with this type of metastatic prostate cancer want to get their genetically targeted therapy as early as possible, and this trial clearly shows the value of rucaparib as a treatment for these men,” Alan H. Bryce, MD, chair of the Division of Hematology and Medical Oncology at the Mayo Clinic and principal investigator of the TRITON3 trial, stated in a press release. “A key point is that rucaparib can replace chemotherapy in this setting. The current standard of care for these men is chemotherapy with docetaxel, and rucaparib is the only PARP inhibitor which has beaten a docetaxel-containing control arm in a clinical trial.”

The multicenter, open-label phase 3 TRITON3 trial enrolled 405 patients with chemotherapy-naïve mCRPC that harbored a deleterious 

 mutation. The study accrued patients who had disease progression following prior treatment with an androgen receptor pathway inhibitor (ARPI), such as abiraterone acetate (Zytiga), enzalutamide (Xtandi), or apalutamide (Erleada).

After a protocol amendment, patients were allowed to have received a qualifying ARPI for either hormone-sensitive or castration-resistant disease; consequently, around 18% of enrolled patients had been treated with an ARPI for metastatic hormone-sensitive disease only.

Patients were randomized to rucaparib or the control arm comprised of physician’s choice of docetaxel, abiraterone acetate, or enzalutamide. Over half (55%) of patients in the control arm were treated with docetaxel. The primary end point of TRITON3 was rPFS per IRR in patients whose tumors harbored a deleterious 

In the ITT population of 405 patients with 

mutations, the median rPFS was 10.2 months versus 6.4 months in the rucaparib arm (n = 270) vs the control arm (n = 135), respectively (HR, 0.61; 95% CI, 0.47-0.80; 

 mutations treated with rucaparib (n = 201), the median rPFS was 11.2 months versus 6.4 months in the physician’s choice control arm (n = 101; HR, 0.50; 95% CI, 0.36-0.69; 

The investigators also did an exploratory analysis of patients whose tumors harbored ATM mutations. In this subgroup, the median rPFS was 8.1 months for the rucaparib arm (n = 69) versus 6.8 months for the control arm (n = 34; HR, 0.97; 95% CI, 0.59-1.52; 

While the overall survival (OS) data are not yet mature, the hazard ratio for OS favored rucaparib in the ITT population and BRCA subgroup. In the ATM subgroup, the hazard ratio for OS favored the control arm, although the confidence interval reflected no significant difference in outcomes between the 2 arms.

Regarding safety, there were no new safety signals in TRITON3 as compared with rucaparib’s label. Grade ≥3 treatment-emergent adverse events (TEAEs) that occurred in at least 5% of patients were anemia/decreased hemoglobin (23.7%), neutropenia/decreased neutrophil count (7.4%), asthenia/fatigue (7.0%), thrombocytopenia/decreased platelet count (5.9%) and increased ALT/AST (5.2%). Overall, TEAEs led to treatment discontinuation in 14.8% vs 21.5% of the rucaparib vs control arms, respectively.

In the press release, Clovis Oncology, the developer of rucaparib, reported that it plans to submit expanded details from this interim analysis at the upcoming Prostate Cancer Foundation Annual Scientific Retreat and submit additional data for presentation at a medical conference early next year.

Rucaparib is currently approved by the FDA for the treatment of adult patients with a deleterious 

mutation (germline and/or somatic)-associated mCRPC who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. The PARP inhibitor is not currently approved for use in the chemotherapy-naïve mCRPC setting.

“This trial demonstrates the potential for rucaparib to treat men with early-stage metastatic castration-resistant prostate cancer,”Karim Fizazi, MD, PhD, principal investigator of the TRITON3 trial, medical oncologist at Gustave Roussy, and a full professor in Oncology at the University of Paris-Saclay, stated in the press release

 “To my knowledge, this is the first time in two decades that a potential new treatment, rucaparib, has shown in a randomized controlled trial radiographic PFS efficacy over an investigator’s choice control arm that included docetaxel chemotherapy, a long-standing standard of care for men with metastatic castration-resistant prostate cancer, and this is excellent news for patients.”

1. TRITON3 Phase 3 Trial Of Rubraca® (Rucaparib) Achieves Primary Endpoint In Men With Metastatic Castration-Resistant Prostate Cancer With BRCA Or ATM Mutations. Published online October 3, 2022. Accessed October 4, 2022. https://bit.ly/3CxMU6O

“Men with this type of metastatic prostate cancer want to get their genetically targeted therapy as early as possible, and this trial clearly shows the value of rucaparib as a treatment for these men,” said Alan H. Bryce, MD, principal investigator of the TRITON3 trial.

Rucaparib delays disease progression in subgroup of chemotherapy-naïve mCRPC

Investigators from Cedars-Sinai Cancer Center in Los Angeles, California have implicated 

 genetic biomarkers in determining whether patients with bladder cancer will respond to anti-PD-1 and PD-L1 immune checkpoint therapies (ICTs).

A prior study from Theodorescu et al found that 

 contributed to anti-PD-1 resistance in animals with various types of cancer.

 For the current study, investigators looked at the DDR gene family again, but in human participants, by analyzing mRNA expressions and gene signatures.

“Our work indicates that these genetic signatures may prove to be tremendously valuable in predicting immunotherapy response in patients with bladder cancer, but also other tumor types. We will continue investigating these biomarkers with the goal of bringing them into clinical use and improving patient outcomes,” senior author Dan Theodorescu, MD, PhD, the director of Cedars-Sinai Cancer Center, said in a news release about the results.

The study authors investigated the impact of 

 on patients with bladder cancer receiving anti-PD-1/L1 immunotherapy by analyzing mRNA expressions of the biomarkers and deriving gene signature scores from transcriptome analysis. The mRNA expressions and gene signature scores were then evaluated using 2 different datasets: BCa The Cancer Genome Atlas (TCGA) program (n = 259) and the IMvigor210 clinical trial (NCT02951767) (n = 298).

-high BCa had indications of a T-cell-inflamed phenotype, whereas 

-high BCa exhibited a non–T-cell-inflamed phenotype. Tumors with a high level of 

 in the IMvigor210 cohort had poor rates of overall survival (OS), but high 

 levels indicated a poorer rate of OS (HR = 1.56 95% CI, 1.20-2.06, 

 < .001) and progression-free survival (HR = 1.77 95% CI, 1.05-3.00, 

 markers were found to be mutually exclusive. Further, high DDR1 tumors were found to be “cold,” meaning they block immune cells from infiltrating, and high 

 tumors were found to be “hot,” meaning that immune cells are usually able to infiltrate to the core of the tumor.

Investigators also found an association between 4 gene signatures modulated by 

 biomarkers and a response to immunotherapy in patients with cancer.

“We found that these gene signatures were clearly associated with response to immunotherapy in bladder cancer and lung cancer tumors in multiple patient groups,” said first author Sungyong You, PhD, a computational biologist at Cedars-Sinai Cancer Center.

According to Theodorescu, the next step would be to validate the findings in a prospective clinical trial. “This could yield new tools that allow clinicians to determine pre-treatment whether given patients will likely respond to anti-PD-1/PD-L1 therapy. They can then proceed with anti-PD-1/PD-L1 therapy for those patients who will derive the most benefit, and offer alternative therapies for patients not likely to respond, improving outcomes for all,” Theodorescu said.

1. You S, Kim M, Hoi XP, et al. Discoidin domain receptor-driven gene signatures as markers of patient response to anti-PD-L1 immune checkpoint therapy. 

. Published online August 3, 2022. doi:10.1093/jnci/djac140

2. Tu MM, Lee FYF, Jones RT, et al. Targeting DDR2 enhances tumor response to anti-PD-1 immunotherapy. 

. 2019;5(2):eaav2437. doi:10.1126/sciadv.aav2437

3. Genetics may predict bladder cancer immunotherapy response. News release. Cedars-Sinai. August 3, 2022. Accessed October 6, 2022. https://www.newswise.com/articles/genetics-may-predict-bladder-cancer-immunotherapy-response?sc=sphr&xy=10016681

“Our work indicates that these genetic signatures may prove to be tremendously valuable in predicting immunotherapy response in patients with bladder cancer, but also other tumor types," says Dan Theodorescu, MD, PhD.

Biomarkers may be predictive of patient response to bladder cancer treatments

, Dana-Farber Cancer Institute, discusses the results of the of the PEACE-1 and ARASENS trials. In the 

, adding abiraterone acetate (Zytiga) and prednisone to androgen-deprivation therapy (ADT) and docetaxel improved overall survival (OS) and radiographic progression-free survival in patients with de novo metastatic castration-sensitive prostate cancer. In the 

, adding darolutamide to standard ADT and docetaxel boosted OS versus ADT/docetaxel alone in patients with metastatic hormone-sensitive prostate cancer.

Stephanie Berg, MD, highlights the key findings of the PEACE-1 and ARASENS trials in patients with metastatic castration-sensitive prostate cancer.

Dr. Stephanie Berg on latest pivotal trials in mCSPC

, chief of the Division of Endourology and Stone Disease and professor of Urology at Northwestern Medicine, is a world leader in holmium laser enucleation of the prostate (HoLEP) for the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia (BPH). 

In this video, Dr. Krambeck takes the viewer step by step through the HoLEP procedure in the OR on a patient with an extremely large prostate (158g) who presented with severe overactive bladder, obstructive voiding symptoms, and urinary incontinence and retention.

Watch Amy E. Krambeck, MD, perform holmium laser enucleation of the prostate (HoLEP) for the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. 

Biomarkers may be predictive of patient response to bladder cancer treatments

Dr. Stephanie Berg on latest pivotal trials in mCSPC

Video: Dr. Amy Krambeck performs HoLEP