Lisette Hilton

Studies are beginning to suggest that COVID-19’s impact on men’s health might go beyond the lungs, heart, and kidneys. According to recently published studies, having COVID-19 could have lasting impacts on fertility and sexual function.

Ranjith Ramasamy, MD, associate professor and director of the University of Miami Miller School of Medicine’s Reproductive Urology Program, is uncovering what he says are clear links between COVID-19 infection and men’s sexual health.

“We know the COVID-19 virus can remain inside the testis long after the initial infection in asymptomatic men. We know the COVID-19 virus can decrease sperm count for up to 3 to 6 months. And we know the COVID-19 virus can affect the blood vessels and be present in the penis up to 7 to 9 months after the initial infection and can lead to erectile dysfunction,” Ramasamy said.

Getting the mRNA COVID-19 vaccine does not appear to impact fertility and should be encouraged, according to Ramasamy, who has published several articles on COVID-19 and men’s sexual health, including the research letter, “Sperm parameters before and after COVID-19 mRNA vaccination” published June 17 in

Findings from early studies looking at male infertility post–COVID-19 infection are concerning, reassuring, conflicting, and inconclusive.

COVID-19 does not appear to get into the semen, according to urologist James M. Hotaling, MD, MS, FECSM, medical director of the fertility integrated practice unit and director of the Men’s Health program at the University of Utah, Salt Lake City.

Hotaling and coauthors in China conducted an observational study of 34 adult Chinese males who received a diagnosis of COVID-19 and found severe acute respiratory syndrome (SARS)-CoV-2 was not detected in the men’s semen 1 month after COVID-19 diagnosis.

Current evidence suggests a low likelihood of SARS-CoV-2 transmission through the seminal fluid. There are limited data characterizing SARS-CoV-2 infection’s impact on male reproductive hormones and semen parameters. And data suggesting SARS-CoV-2 gets into testes are inconclusive, according to Hotaling.

Data regarding the short- and long-term impacts of SARS-CoV-2 on male reproductive health remain largely inconclusive and need further long-term study, Hotaling and colleagues reported in a review of the literature published April 2021 in 

But Ramasamy and other investigators are finding causes for concern.

A study published earlier this year in the 

 by Ramasamy et al looked at testis tissue collected from autopsies of 6 COVID-19 positive and 3 COVID-19 negative men. The investigators found 3 of the 6 COVID-19–positive biopsies had normal spermatogenesis and 3 had impaired spermatogenesis. Electron microscopy showed the COVID-19 virus in testis tissue of 1 COVID-19–positive autopsy case.

The novel COVID-19 virus has an affinity for angiotensin converting enzyme-2 (ACE-2) receptors. Since ACE-2 receptor expression is high in the testes, the study authors hypothesized that COVID-19 can be present in testes tissue of infected patients. This study suggests that the male reproductive tract, specifically the testes, may be the target of COVID-19 infection. They found an inverse association between ACE-2 receptor levels and spermatogenesis, suggesting a possible mechanism of how COVID-19 can cause infertility, according to the study.

Investigators in China also found evidence that SARS-CoV-2 can infect the testis and germ cells, suggesting a potential impact on spermatogenesis and male fertility.

“Nevertheless, further study is essential to reveal the underlying mechanism of SARS-CoV-2 infection of testicular cells and the correlation of testis infection with the clinical course of COVID-19,” according to the correspondence published December 14, 2020, in 

Although more quality research is needed to confirm these results, the findings make sense when one thinks about COVID-19 infection basics, according to Hossein Sadeghi-Nejad, MD, FACS, professor of Surgery/Urology at Rutgers New Jersey Medical School and Hackensack University Medical Center.

Infection from SARS-CoV-2 causes an exaggerated inflammatory response leading to immunosuppression. The body releases cytokines that mainly affect lung tissue but also lead to extrapulmonary effects, he said.

For example, some studies are showing overall testosterone levels can be lower in patients who get COVID-19. Investigators of a single-center cohort study of patients with COVID-19 found lower testosterone concentrations during hospitalization were associated with increased disease severity and inflammation in men.

Still unclear is whether the decrease in testosterone is an adaptive or maladaptive COVID-19 response.

The reason for the likelihood of lower testosterone levels in COVID-19 patients is that SARS CoV-2 gets into the system is through ACE-2, which has been expressed in Leydig cells and Sertoli cells, according to Sadeghi-Nejad.

Damage to Leydig cells may lead to testosterone deficiency, he said.

There are about 2 dozen peer-reviewed articles containing research or findings regarding COVID-19 and erectile dysfunction (ED), according to Martin Gross, MD, assistant professor at Dartmouth-Hitchcock Medical Center and codirector of the Dartmouth-Hitchcock Men’s Health Center.

“They predominantly include case reports, observational studies, survey data, expert opinions, and review articles. These types of articles tend to be on the lower end of scientific rigor,” Gross said. “We don’t know much about the relationship between ED and COVID-19 at this point.”

A study by Ramasamy et al, published in July in the 

nalyzing penile tissue from COVID-19 patients who recovered and subsequently developed ED, was novel and interesting, according to Gross.

It was the first study to demonstrate the presence of the COVID-19 virus in the penis up to 9 months after the initial infection and suggests that endothelial dysfunction from the virus could contribute to ED.

Omer Raheem, MD, MSc, assistant professor of urology and director of men’s health at Tulane University School of Medicine, New Orleans, Louisiana, said he found it interesting that 1 of the 2 men Ramasamy and colleagues studied was hospitalized for COVID-19 infection, whereas the other had only mild COVID-19 symptoms, yet both men developed severe erectile dysfunction.

This study suggests that widespread endothelial cell dysfunction from COVID-19 infection can contribute to erectile dysfunction. Larger prospective studies are warranted to further validate this finding, Raheem said.

“From patient’s perspective, albeit not conclusive, there is some evidence suggesting the potentially negative impact of COVID-19 infection on male reproductive function and overall men’s health. Likewise, COVID-19–infected or COVID-19–recovered men should be aware of the possible risk of developing erectile dysfunction, male infertility, and hypogonadism, owing to the adverse effect of the SARS-CoV-2 virus on testicular Sertoli and Leydig cells via ACE-2 binding. And obviously those symptomatic men should seek urologic consultation to evaluate and treat these conditions,” Raheem said.

Although the link between COVID-19 infection, endothelial damage, and ED is interesting, the finding should be further evaluated in larger studies and viewed cautiously, according Sadeghi-Nejad.

“Endothelial damage is not restricted to COVID-19. Endothelial dysfunction is seen in many of our patients who have erectile dysfunction, which we know to be a neurovascular problem,” Sadeghi-Nejad said.

There are conflicting data about whether sexual activity increased or decreased during the pandemic, according to Sadeghi-Nejad.

Many surveys on sexual activity during quarantining suggest decreased activity, possibly because the studies included younger patients with children living at home. Other studies on older patients showed increased activity.

Interestingly, investigators studying US sales of phosphodiesterase-5 (PDE5) inhibitors show sales of the medications spiked during lockdowns.

Turkish authors of a paper published earlier this year in 

 reported a significant increase in andrological diagnoses during the pandemic, compared with before it.

“There was a statistically significant increase in the number of patients diagnosed with male reproductive or sexual health problems during the COVID-19 pandemic period,” according to the authors. “The number of patients diagnosed with erectile dysfunction during the pandemic was also significantly higher than [in] the pre–COVID-19 pandemic period.”

The paper’s authors suggest that although these problems are multifactorial, psychogenic factors might be a significant trigger.

In other research, the PDE5 inhibitors men use to treat erectile dysfunction could also treat COVID-19. These medications, the authors wrote, have anti-inflammatory, antioxidant, immune response regulation, and antiapoptotic properties.

“A lot of the paper was theoretical but solidly grounded in physiology and pharmacology,” Gross said. “These studies are all interesting to some degree, but they are snapshots in time that may lose relevance down the road.”

Counseling patients about COVID-19’s potential impact on sexual health and fertility might start with encouraging patients to get vaccinated.

“I recommend that all couples trying to conceive get the vaccine. And that it is safe,” Hotaling said.

Men who have acute COVID-19 infections and see a decline in spermatogenesis should consider waiting 3 to 6 months before planning fertility treatment so their sperm counts can recover, according to Ramasamy.

Sadeghi-Nejad cites American Society of Reproductive Medicine recommendations regarding shared decision-making and detailed discussions, including not withholding the vaccine from patients who are planning to conceive, those who are already undergoing fertility treatment, and pregnant patients. These groups should be encouraged to receive vaccination if there are no other contraindications.

Gross, however, said he questions the value of further research on the link between ED and COVID-19, and a COVID-19 diagnosis does not change his approach to ED treatment.

“It would be presumptuous to think that our little corner of medicine has any relevance to the bigger COVID-19 picture. And lots of conditions cause ED; let’s try and tackle those first,” Gross said. “I have never found a good reason to wait to treat any patient’s erectile dysfunction. If a patient has a problem, hears his options, and is healthy enough and wants to proceed with some or all of these options, then I’m happy to help. If patients aren’t healthy enough or otherwise prepared to move forward with treatment, then we can wait until they’re ready.”

Questions remain about how the virus invades the immune system and can stay in organs for such a long time, as well as whether any impact from COVID-19 on male fertility or sexual function is permanent, according to Ramasamy.

More data should be coming out soon, according to Hotaling.

“Some of the big IVF groups are tracking their outcomes where the men or women have had COVID-19. A lot of these big claims databases will release their data from 2020 sometime between now and the end of the year,” Hotaling said. “There are a lot of studies out of Europe that I’ve seen tracking cohorts of patients who had COVID-19.”

Ongoing and long-term studies to evaluate the potential impact of the COVID-19 infection on men’s health are needed as we emerge from COVID-19 pandemic and monitor the novel COVID-19 Delta variant, Raheem said.

1. Gonzalez DC, Nassau DE, Khodamoradi K, et al. Sperm parameters before and after COVID-19 mRNA vaccination.

 Published online June 17, 2021. doi:10.1001/jama.2021.9976

2. Pan F, Xiao X, Guo J, et al. No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019. 

 2020;113(6):1135-1139. doi:10.1016/j.fertnstert.2020.04.024

3. Patel DP, Punjani N, Guo J, Alukal JP, Li PS, Hotaling JM. The impact of SARS-CoV-2 and COVID-19 on male reproduction and men’s health. 

 2021;115(4):813-823. doi:10.1016/j.fertnstert.2020.12.033

4. Achua JK, Chu KY, Ibrahim E, et al. Histopathology and ultrastructural findings of fatal COVID-19 infections on testis. 

 2021;39(1):65-74. doi:10.5534/wjmh.200170

5. Ma X, Guan C, Chen R, et al. Pathological and molecular examinations of postmortem testis biopsies reveal SARS-CoV-2 infection in the testis and spermatogenesis damage in COVID-19 patients. 

. 2021;18(2):487-489. doi:10.1038/s41423-020-00604-5

6. Dhindsa S, Zhang N, McPhaul MJ, et al. Association of circulating sex hormones with inflammation and disease severity in patients with COVID-19.

. 2021;4(5):e2111398. doi:10.1001/jamanetworkopen.2021.11398

7. Stolk RF, van Leeuwen HJ, Kox M, et al. The chicken or the egg: low testosterone predisposes for COVID-19 or COVID-19 induces a decrease in testosterone? 

 2021;25(1):237. doi:10.1186/s13054-021-03664-9

8. Kresch E, Achua J, Saltzman R, et al. COVID-19 endothelial dysfunction can cause erectile dysfunction: histopathological, immunohistochemical, and ultrastructural study of the human penis. 

. 2021;39(3):466-469. doi:10.5534/wjmh.210055

9. Hernandez I, Gul Z, Gellad WF, Davies BJ. Marked increase in sales of erectile dysfunction medication during COVID-19. 

10. Duran MB, Yildirim O, Kizilkan Y, et al. Variations in the number of patients presenting with andrological problems during the coronavirus disease 2019 pandemic and the possible reasons for these variations: a multicenter study. 

 2021;9(1):100292. doi:10.1016/j.esxm.2020.100292

11. Mostafa T. Could oral phosphodiesterase 5 inhibitors have a potential adjuvant role in combating COVID-19 infection?. 

2021;9(1):15-22. doi:10.1016/j.sxmr.2020.08.006

12. ASRM issues statement on COVID-19 vaccines, joins other OB/GYN groups on community-wide statement. News release. American Society for Reproductive Medicine. Dec 16, 2020. Accessed July 13, 2021. https://bit.ly/3BbJ5Bq

Articles

According to recently published studies, having COVID-19 could have lasting impacts on fertility and sexual function.

COVID-19 and men’s health: What we know so far

Treating men with metastatic hormone-sensitive prostate cancer with enzalutamide (Xtandi) plus androgen deprivation therapy (ADT) can improve progression-free survival (PFS) if patients have bone and/or lymph node metastases. The combination, however, appears to be less effective among men who have visceral patterns of spread, according to a study published in the 

The pattern of metastatic spread in prostate cancer has clear prognostic implications. What has not been understood is how a pattern of spread impacts potential benefits of adding more potent androgen receptor inhibition to ADT, according to study author Andrew Armstrong, MD, professor of medicine, associate professor in pharmacology and cancer biology, and professor in surgery at Duke University School of Medicine, in Durham, North Carolina.

“Here we show that there are clear benefits in delaying radiographic progression or death, prostate-specific antigen (PSA) progression, and other outcomes in the largest groups of men with metastatic hormone-sensitive prostate cancer and lymph node and bone metastases,” Armstrong said. “Men with organ (visceral, such as lung and liver sites) metastases were found to have a poor prognosis, and this small subgroup did not clearly have a delay in radiographic progression with the addition of enzalutamide. Much of this was driven by the poor outcomes of men with liver metastases, whereas men with lung metastases only had a more favorable prognosis and had improved outcomes with enzalutamide/ADT.”

The international group of investigators conducted a post hoc analysis of men with metastatic hormone-sensitive prostate cancer from the phase 3 ARCHES trial (NCT02677896). Investigators randomized 1146 men with metastatic hormone-sensitive prostate cancer to 160 mg/day of enzalutamide plus ADT or placebo and ADT, with the primary end point being radiographic PFS. There were 513 patients with bone metastases only, making up the largest study subgroup. Among the other subgroups, 351 men had bone and lymph node metastases, 154 had lymph node metastases only, and 128 had visceral plus or minus bone or lymph node metastases.

The study results found benefits of enzalutamide and ADT in men with node only and bone plus or minus lymph node metastases and lung metastases, regardless of disease volume.

According to Armstrong, the limited benefits in men with liver metastases suggests that it may be less androgen receptor-dependent, which calls for new strategies to understand this pattern of spread at the molecular level to reduce death and negative experiences from prostate cancer.

“Liver metastases were already known to be associated with a poor prognosis in metastatic castrate-resistant prostate cancer, but our data add to this importance in earlier disease settings,” he said.

For now, urologists and oncologists should consider a liver biopsy to evaluate for neuroendocrine or small cell prostate cancer as per National Comprehensive Cancer Network and American Urological Association guidelines, according to Armstrong.

“Such men are more likely to benefit from docetaxel and ADT in this setting, given the results of the CHAARTED [NCT00309985] and STAMPEDE trials [NCT00268476],” he said.

Radiographic PFS is a clinically relevant end point that urologists and other physicians use to make treatment decisions that impact patients’ lives in practice, Armstrong said.

There are major treatment implications when a patient with metastatic hormone-sensitive prostate cancer progresses to metastatic castration-resistant prostate cancer, requiring changes to strategies, given the abundance of approved agents in the metastatic castration-resistant prostate cancer setting. According to Armstrong, with the profound improvements in radiographic PFS observed in ARCHES, the FDA approved enzalutamide in the metastatic hormone-sensitive prostate cancer setting.

“Patients were offered cross-over and open-label access to enzalutamide,” he said. “Enzalutamide is known to improve survival in castrate-resistant prostate cancer patients already, and continuing this study to a survival primary end point was not reasonable given the results of the ENZAMET trial [NCT02446405], which demonstrated improved survival with enzalutamide in this setting.”

According to Armstrong, There are downsides to adding the androgen receptor inhibitor to treatment. Enzalutamide adds adverse effects to ADT alone, including fatigue, high blood pressure, loss of bone density, fracture risks, muscle loss, fall risk, and hot flushes. Some men experience cognitive issues with fatigue. Providers can help patients reduce these adverse effects through attention to exercise, bone health, cardiovascular risk factors, and blood pressure monitoring.

The work to find optimal treatments for these patients is far from over.

“Although enzalutamide, abiraterone, and apalutamide each extends life in men with metastatic hormone-sensitive prostate cancer, these patients still progress after several years of treatment, and new therapies are needed,” Armstrong said. “Men with liver metastases progress the fastest, and this group represents the largest unmet medical need where research is needed to understand how prostate cancers favor the liver microenvironment and how we can improve survival in this setting and prevent liver metastases.”

Future studies, he said, will examine whether enzalutamide and ADT after completion of docetaxel and ADT in these patients with poor-prognosis, visceral metastatic hormone-sensitive prostate cancer can extend survival.

For now, men with metastatic hormone-sensitive prostate cancer should be educated about their prognosis based on their disease risk and pattern of spread, Armstrong said.

: Astellas Pharma and Pfizer funded the study. Andrew Armstrong, MD,

is a consultant with Astellas, Pfizer, Bayer, and Janssen.

1. Armstrong AJ, Shore ND, Szmulewitz RZ, et al. Efficacy of enzalutamide plus androgen deprivation therapy in metastatic hormone-sensitive prostate cancer by pattern of metastatic spread: ARCHES post hoc analyses. 

 Published online December 28, 2020. doi:10.1097/JU.0000000000001568

"Here we show that there are clear benefits in delaying radiographic progression or death, [PSA] progression, and other outcomes in the largest groups of men with metastatic hormone-sensitive prostate cancer and lymph node and bone metastases,” says Andrew Armstrong, MD.

Pattern of metastatic spread impacts whether enzalutamide plus ADT improves PFS in prostate cancer

F-fluciclovine (Axumin) PET/CT changed clinical management in 62% of patients with biochemically recurrent prostate cancer, according to real-world data from an academic center published in 

Twelve percent of patients with negative results on conventional imaging had lesion localization on 

F-Fluciclovine PET/CT remains a useful diagnostic tool in the workup of patients with BCR PC,” authors concluded.

F-fluciclovine scans of 165 consecutive men with biochemical recurrence after receiving primary definitive treatment. Among these patients, 102 had undergone prostatectomy as their primary treatment and 63 had received radiotherapy.

F-fluciclovine PET had an overall positivity rate of 67%. There was an expected incremental increase in the positivity rate as patients’ PSA levels increased, from a low of 15% among patients with a PSA <0.5 ng/ml, to a high of 94% among patients with a PSA ≥5 ng/ml. Overall, the results of 

F-fluciclovine PET resulted in a change in clinical management in 162 patients.

Additional findings were assessed in 33 patients who received 1 or more other PET imaging, including 

Ga-RM2 PET/MRI (5 patients). Among 14 of these patients, changes to the patient’s treatment plan were made based on further PET imaging with a different radiopharmaceutical.

Previous results from a study published in the 

F-fluciclovine PET/CT detects metastases better than conventional imaging in patients with high-risk prostate cancer.

In this clinical trial, 57 patients with high-risk prostate cancer were staged by conventional imaging, including 99mTc-methylene diphosphonate bone scanning and CT or MRI. They then underwent 

F-fluciclovine PET/CT, followed by robotic radical prostatectomy and extended pelvic lymph node dissection.

F-fluciclovine PET/CT detected nodal metastasis with a sensitivity of 55.3% and a specificity of 84.8% in each patient. PET imaging sensitivity and specificity were 54.8% and 96.4%, respectively, per region (right and left pelvis, presacral and nonregional), according to the paper.

The advanced imaging had 22% greater sensitivity for each patient compared with conventional imaging. And 

F-fluciclovine PET/CT detected regional and nonregional metastases in patients with prostate cancer that went undetected with conventional imaging. PET/CT detected metastases in 7 more patients and 22 more regions and identified distant disease or other cancers in 4 patients.

In the paper, the authors noted that their findings were in line with results of other studies published in the literature.

The FDA approved the radiopharmaceutical 

F-fluciclovine in May 2016 for PET imaging in men with suspected prostate cancer recurrence based on elevated PSA levels following prior treatment.

F-Fluciclovine PET/CT in Biochemically Recurrent Prostate Cancer: an Academic Center Experience Post FDA Approval [published online ahead of print January 19, 2021]. 

2. Alemozaffar M, Akintayo AA, Abiodun-Ojo OA, et al. [

F]Fluciclovine positron emission tomography/computerized tomography for preoperative staging in patients with intermediate to high risk primary prostate cancer. 

. 2020;204(4):734-740. doi:10.1097/JU.0000000000001095

Twelve percent of patients with negative results on conventional imaging  had lesion localization on 18F-fluciclovine PET.

Real-World data show utility of 18F-fluciclovine PET/CT in biochemically recurrent prostate cancer

Urology innovation and progress were not completely lost in 2020. In fact, urologists say that important advances in the specialty happened, with the coronavirus disease 2019 (COVID-19) pandemic triggering some positive, long-lasting changes in patient care.

Looking back at prostate cancer treatments

Urology took big steps to further precision medicine in 2020, according to Leonard G. Gomella, MD, the Bernard W. Godwin Jr Professor of Prostate Cancer and chairman of the Department of Urology at Thomas Jefferson University and Hospital in Philadelphia, Pennsylvania.

The FDA approved 2 drugs representing a new class of medications for refractory metastatic castration-resistant prostate cancer called poly (ADP-ribose) polymerase (PARP) inhibitors. Treatment with the approved drugs rucaparib (Rubraca) and olaparib (Lynparza) is based on identifying DNA repair pathway deficits in the tumors using genomic and genetic analyses.

“If patients fail standard treatments, but there is an identified DNA repair pathway gene mutation in their inherited germline or based on somatic tumor or metastasis testing, such as a mutated 

 gene, they are eligible for this new class of oral agents,” Gomella said.

The American Urological Association (AUA) released a new advanced prostate cancer guideline in 2020.

 One of the biggest take-home messages in the new document is that clinicians should offer PARP inhibitors to patients with these deleterious or suspected deleterious germline or somatic repair gene mutations, Gomella said.

Standout research in prostate cancer published in 2020 includes the CARD study (NCT02485691),

 which looks at using the previously approved chemotherapy drug cabazitaxel (Jevtana). Results suggest a significant improvement in overall survival in patients with metastatic castration-resistant prostate cancer who had failed docetaxel. Cabazitaxel treatment resulted in an improvement in these patients versus using an androgen receptor pathway blocker, such as abiraterone (Zytiga) or enzalutamide (Xtandi).

“This is important because it shows this chemotherapy can be active after failure of another chemotherapy and give you improved overall survival, and helps clarify some of the questions concerning sequencing medications in advanced prostate cancer,” Gomella said.

Still investigational but under priority review at the FDA for treatment of advanced prostate cancer, relugolix is an oral GnRH antagonist with a superior sustained castration rate through week 48, according to a phase 3 study in the 

 Results also show a reduced risk of major adverse cardiovascular events compared with leuprolide.

Theranostics is an important area of research for patients with prostate cancer. The technology not only identifies the metastasis but also kills the cancer with a therapeutic radioisotope such as lutetium-177. In the TheraP trial (NCT03392428), the first randomized trial to compare a theranostic known as lutetium-177–labeled prostaste-specific membrane antigen (Lu-PSMA) with refractory cancer, the majority of patients showed greater than a 50% decline in PSA, according to results presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program.

“The phase 3 VISION trial [NCT03511664] will tell us more,” Gomella said. “VISION is comparing standard of care with or without Lu-PSMA for patients with metastatic castration-resistant prostate cancer who have disease progression on docetaxel and enzalutamide or abiraterone acetate.”

In addition, on December 1, 2020, the FDA approved the first drug for positron emission tomography imaging of PSMA-positive lesions in men with prostate cancer, Gallium 68 PSMA-11 (Ga 68 PSMA-11).

Pembrolizumab (Keytruda) is the first systemic treatment approved for non–muscle-invasive bladder cancer (NMIBC). Pembrolizumab was approved in 2020 based on the KEYNOTE-057 trial (NCT02625961), which looked at patients who had BCG-unresponsive, high-risk NMIBC.

 Patients had a 41% carcinoma in situ response rate, and the response lasted a little over 1 year and 4 months, with almost half the patients having a complete response after about 12 months, according to Gomella.

The FDA approved the reverse-thermal hydrogel mitomycin (Jelmyto), a first-in-class treatment for adult patients with low-grade upper tract urothelial cancer. The landmark approval of this proprietary sustained-
release hydrogel-based platform technology is based on positive results of a 59% complete response rate from the phase 3 OLYMPUS trial (NCT02793128).

“We never really had anything to do for these people before except for repeated biopsies and ablation or, unfortunately, taking out their kidney and ureter,” Gomella said.

Gomella served as a coauthor of a recently published 

study that evaluated the novel intravesical gene-mediated therapy nadofaragene firadenovec for patients with high-grade, BCG-unresponsive NMIBC.

 In that study, the investigational agent induced complete responses in more than half of patients.

Treating overactive bladder or incontinence

There were significant overactive bladder treatment advances in 2020, and many more are on the horizon, according to Priya Padmanabhan, MD, MPH, professor of urology at Oakland University William Beaumont School of Medicine in Rochester, Michigan.

“There was a period of stagnancy in overactive bladder treatment, yet we are now bursting at the seams with new ideas and technologies,” Padmanabhan said.

In pharmacotherapy, the only alternative to anticholinergics had been mirabegron (Myrbetriq), a beta-3 agonist.

The FDA has accepted a new drug application by Urovant for vibegron, a small molecule beta-3 agonist. Data from the Empowur study (NCT03492281), a phase 3, double-blind, randomized trial, supported the approval.

 Vibegron is being studied for treatment of overactive bladder in patients with benign prostatic hyperplasia (BPH) at multiple sites, including Beaumont Hospital in Royal Oak, Michigan. Full FDA approval is just a matter of time, according to Padmanabhan.

Sacral neuromodulation has 2 systems challenging norms in 2020. Medtronic and Axonics Modulation Technologies both have MRI-safe and rechargeable options, according to Padmanabhan.

“This is a culmination of the [Axonics ARTISAN-SNM trial (NCT03327948)].

 Data [are] starting to be collected in Medtronic’s ELITE study [NCT04506866] of the new InterStim Micro system. We have been involved with both trials,” Padmanabhan said. “Axonics has recently won FDA approval for its next-generation rechargeable neurostimulator, a rechargeable battery requiring less time to charge.”

There is much interest in creating an implantable tibial nerve stimulator. Response would ideally be achieved quicker and without the repetitive visits required by standard percutaneous tibial nerve stimulation. According to Padmanabhan, there are a number of implants under consideration: BlueWind’s RENOVA, Valencia’s eCoin, Micron Medical Corporation’s PROTECT, and the Bioness StimRouter.

Urovant Sciences presented results of its phase 1 trial (NCT04211831) on URO-902, a gene therapy using a naked DNA plasmid vector that is delivered directly into the bladder.

 Padmanabhan and colleagues are participating in the phase 2 trial.

The BTL EMSELLA chair delivers high-intensity, focused electromagnetic perineal stimulation to patients who remain fully clothed. This stimulation activates the motor neurons in the pelvic floor. There is now active enrollment to study the effects on all types of incontinence.

“This involves a sham and an active arm with treatment administered twice weekly for 6 weeks total,” Padmanabhan said. “All in all, there [have] been tremendous therapeutic movement and research on overactive bladder in 2020.”

The COVID-19 pandemic did not stop Steven A. Kaplan, MD, and colleagues from launching the Society of Benign Prostate Disease (https://societyofbenign.godaddysites.com), the first BPH specialty society in the United States, according to Kaplan, who is professor of urology and director of the Men’s Wellness Program at Icahn School of Medicine at Mount Sinai, New York, New York.

“We will have a virtual meeting in 2021,” he said.

In other BPH developments, the FDA approved Medi-Tate’s iTind device.

“It is a device you leave in the prostate for about 5 days, [during which] it creates incisions at the prostate. Then you remove it and, in theory, it leaves the channels more open,” Kaplan said.

Medicare is now reimbursing for Aquablation, which uses a heat-free waterjet controlled by robotic technology to remove prostate tissue.

A promising device in the phase 3 trial EVEREST-I (NCT03423979) is the Optilume BPH Prostatic Drug Coated Balloon Dilation Catheter, according to Kaplan, the study’s principal investigator.

“The Optilume device is a balloon dilation of the prostate that uses paclitaxel to diminish the inflammatory response. It is a 2-for-1 therapy, basically. The data are some of the best we have seen,” Kaplan said.

One of the year’s standout studies published in 

 was “Mirabegron vs placebo add-on therapy in men with overactive bladder symptoms receiving tamsulosin for underlying benign prostatic hyperplasia: a safety analysis from the randomized, phase 4 plus study.”

 The authors reported no unexpected safety concerns in men receiving tamsulosin (Flomax) for lower urinary tract symptoms associated with BPH who subsequently received mirabegron add-on therapy.

Kaplan noted that the AUA released an amended BPH surgical management guideline in 2020,

 and in 2021 the guideline will be revised again to include medical therapy.

Curtailed plans to take on capital equipment put a damper on new device trialing for kidney stones during the pandemic, according to Brian R. Matlaga, MD, MPH, professor of urology and director of the Gerald and Helen Stephens Center for Stone Disease at the James Buchanan Brady Urological Institute at Johns Hopkins University School of Medicine in Baltimore, Maryland.

“A device that was introduced in 2019 but came into widespread use this year is the thulium fiber laser [Soltive, Olympus],” Matlaga said. “The thulium fiber is an entirely new way to generate laser energy. It has been reported to allow us to treat certain kidney stones potentially
in a more efficient fashion, but the clinical data are not there quite yet.”

There have been several publications in peer-reviewed literature about managing urologic diseases, including stone disease, during a pandemic.

“If our numbers do increase, these shared experiences could serve as playbooks for us in the field of how we’re going to manage stone or other urologic patients,” Matlaga said. “We have learned that the clinical enterprise cannot be shut down completely. The nature of stone disease is that there are acute events that do require treatment even in the midst of a pandemic at its peak. These studies provide a way to stratify the urgency of an intervention with predefined criteria.”

There also is growing interest in intrarenal pressure during endoscopic stone management.

“We know that during ureteroscopy that we can generate pressures within the kidney through the use of pressurized irrigation. We do not, as a field, really have a clear understanding of the effects of those pressures. We have seen several studies coming out looking at various impacts of intrarenal pressure or how to measure intrarenal pressure,” Matlaga said.

Developments continue in treating sexual dysfunction

Device and drug approvals in the sexual dysfunction arena slowed in recent months, but there were important developments in research, according to Arthur L. Burnett II, MD, MBA, the Patrick C. Walsh Distinguished Professor of Urology and professor of oncology at Johns Hopkins University School of Medicine.

“One sign of the times has to do with the impact of the COVID-19 virus on sexual health,” Burnett said. “I think there has been a great deal of emphasis in the arena of mental health and its impact in terms of relationships and how individuals are interacting. This question of how do we deal with the impact of the virus on relationships, sexual activity, the risk for transmission, etc, has [received] attention in recent months.”

Burnett said there is anecdotal evidence that the implant business has increased in recent months, and device companies such as Boston Scientific are trying to better understand why.

“I am one of the high implanters and am working with Boston Scientific to mine those data,” Burnett said. “We speculate that it may be some of the cases were deferred or delayed. Another possibility is that people are working from home and can recover without having to take a lot of time off. Maybe another factor is that people are recognizing that sexual activity is important, especially if the world is going to end.”

Another research trend focuses on the effect of health care disparities and racial inequities on sexual dysfunction. That research previously was more centered on disparities in heart disease and cancer.

“[Although] not fully measured or documented, I do think there is the appreciation out there that disparities exist in regard to sexual medicine and health care,” he said. “These are some of the phenomena that I am seeing and hearing in conversations, webinar attendance, talking with specialists and industry.”

The AUA, in conjunction with the Sexual Medicine Society of North America, recently rolled out a guideline for disorders of ejaculatory function,

 and a new priapism guideline is in the works, according to Burnett.

COVID-19 forced physicians to embrace telemedicine, a need long overdue, according to Padmanabhan.

“In attempting to reduce transmission, we made radical changes in the way we provide quality care for our [patients with overactive bladders],” she said. “[Through telemedicine,] I was able to survey symptoms, recommend medications, and assess success with subjective questions and quality-of-life questionnaires. If there is any concern, patients may be invited to come in for physical exam and testing. With this change, there has been an increase in patient accessibility, reaching individuals with physical and financial limitations that we could not have reached as easily before.”

The true impact of delays in urologic care have yet to be sorted. But indications are that some men with prostate cancer might be more resilient than other patients with cancer during a pandemic, according to Gomella.

The National Comprehensive Cancer Network reported minimal harm is expected with delays in prostate cancer care or treatment taking from 3 to 6 months, especially when weighed against the risk of mortality of COVID-19.

There is a recent finding related to the pandemic that might surprise most urologists and their patients with prostate cancer. Although patients with most types of cancer have an increased risk of severe acute respiratory syndrome coronavirus 2 (the virus that causes COVID-19) infection compared with patients without cancer, patients with prostate cancer receiving androgen ablation had a significantly lower infection risk. This resulted in a series of clinical trials using androgen ablation in the battle against COVID-19, and these have been reviewed in an editorial by Gomella titled “COVID-19 and the prostate cancer connection,” published in October in the

1. Lowrance WT, Breau RH, Chou R, et al. Advanced prostate cancer: AUA/ASTRO/SUO guideline part I. 

 Published online September 22, 2020. doi:10.1097/JU.0000000000001375

2. Lowrance WT, Breau RH, Chou R, et al. Advanced prostate cancer: AUA/ASTRO/SUO guideline part II. 

Published online September 22, 2020. doi:10.1097/JU.0000000000001376

3. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. 

2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206

4. Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. 

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5. Hofman MS, Emmett L, Sandhu SK, et al. TheraP: a randomised phase II trial of 177Lu-PSMA-617 (LuPSMA) theranostic versus cabazitaxel in metastatic castration resistant prostate cancer (mCRPC) progressing after docetaxel: initial results (ANZUP protocol 1603). Paper presented at: 2020 American Society of Clinical Oncology Virtual Scientific Program; May 29-31, 2020; virtual. Accessed November 13, 2020. https://bit.ly/36EWjbq

Experts in prostate cancer, bladder cancer, kidney stones, OAB/incontinence, BPH, and sexual dysfunction recap all the key advances from 2020.

Lisette Hilton

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