Urology in 2020: PARP inhibitors make a splash as COVID-19’s impact is felt throughout specialty

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

Leonard G. Gomella, MD

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 BRCA1 or BRCA2 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.^1,2 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),³ 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 New England Journal of Medicine.⁴ 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.⁵

“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).⁶

Bladder cancer treatments advance

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.⁷ 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).⁸

“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 Lancet Oncology study that evaluated the novel intravesical gene-mediated therapy nadofaragene firadenovec for patients with high-grade, BCG-unresponsive NMIBC.⁹ In that study, the investigational agent induced complete responses in more than half of patients.

Treating overactive bladder or incontinence

Priya Padmanabhan, MD, MPH

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.¹⁰ 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)].¹¹ 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.¹² 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.”

Making strides in BPH

Steven A. Kaplan, MD

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 Urology 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.”¹³ 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 2020,¹⁴ and in 2021 the guideline will be revised again to include medical therapy.

What’s new in stone disease

Brian R. Matlaga, MD, MPH

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

Arthur L. Burnett II, MD, MBA

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,¹⁵ and a new priapism guideline is in the works, according to Burnett.

The pandemic effect

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-19.¹⁶

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 Canadian Journal of Urology.¹⁷

References

1. Lowrance WT, Breau RH, Chou R, et al. Advanced prostate cancer: AUA/ASTRO/SUO guideline part I. J Urol. 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. J Urol. 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. N Engl J Med. 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. N Engl J Med. 2020;382(23):2187-2196. doi:10.1056/NEJMoa2004325

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

6. FDA approves first PSMA-targeted PET imaging drug for men with prostate cancer. Press release. FDA. December 1, 2020. Accessed December 1, 2020. https://bit.ly/3fWUOcN

7. Balar AV, Kulkarni GS, Uchio EM, et al. Keynote 057: phase II trial of pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG). Paper presented at: 2019 Genitourinary Cancers Symposium. February 14-16, 2019. Accessed November 13, 2020. https://bit.ly/2IM6UJq

8. Kleinmann N, Matin SF, Pierorazio PM, et al. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial. Lancet Oncol. 2020;21(6):776-785. doi:10.1016/S1470-2045(20)30147-9

9. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncology. Published online November 27, 2020. doi:10.1016/S1470-2045(20)30540-4

10. Staskin D, Frankel J, Varano S, et al. International phase III, randomized, double-blind, placebo and active controlled study to evaluate the safety and efficacy of vibegron in patients with symptoms of overactive bladder: EMPOWUR. J Urol. 2020;204(2):316-324. doi:10.1097/JU.0000000000000807

11. Benson K, McCrery R, Taylor C, et al. One-year outcomes of the ARTISAN-SNM study with the Axonics System for the treatment of urinary urgency incontinence. Neurourol Urodyn. 2020;39(5):1482-1488. doi:10.1002/nau.24376

12. Rovner E, Chai TC, Jacobs S, et al. Evaluating the safety and potential activity of URO-902 (hMaxi-K) gene transfer by intravesical instillation or direct injection into the bladder wall in female participants with idiopathic (non-neurogenic) overactive bladder syndrome and detrusor overactivity from two double-blind, imbalanced, placebo-controlled randomized phase 1 trials. Neurourol Urodyn. 2020;39(2):744-753. doi:10.1002/nau.24272

13. Herschorn S, McVary KT, Santos JC, et al. 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. Urology. Published online October 10, 2020. doi:10.1016/j.urology.2020.09.040

14. Parsons JK, Dahm P, Köhler TS, et al. Surgical management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: AUA guideline amendment 2020. J Urol. 2020;204(4):799-804. doi:10.1097/JU.0000000000001298

15. Shindel AW, Althof SE, Carrier S, et al. Disorders of ejaculation: an AUA/SMSNA guideline. June 25, 2020. Accessed November 13, 2020. https://bit.ly/32IcbJ2

16. Care of prostate cancer patients during the COVID-19 pandemic: recommendations of the NCCN. National Comprehensive Cancer Network. Accessed November 13, 2020. https://bit.ly/3pqS9MT

17. Gomella LG. COVID-19 and the prostate cancer connection. Can J Urol. 2020;27(5):10346