Jason M. Broderick

During the 2020 AUA Virtual Experience, Steven A. Kaplan, MD, explained the changes incorporated into the 2020 AUA Guideline on Benign Prostatic Hyperplasia (BPH):

 Surgical Management of BPH/Lower Urinary Tract Symptoms (LUTS)

“This guideline [on LUTS secondary to BPH] should be used in conjunction with recent systematic literature reviews and an understanding of the patient’s treatment goals. In all cases, the patient’s preferences and personal goals should be considered when choosing therapy,” said Kaplan, a member of the AUA BPH Surgical Panel responsible for the guideline, and a professor of urology at the Icahn School of Medicine.

Overall, the guideline comprises 24 statements divided into 15 categories. The broader categories are Evaluation and Preoperative Testing, Surgical Therapy, and Medically Complicated Patients.

The treatment-specific categories are Transurethral Resection of the Prostate (TURP); Simple Prostatectomy; Transurethral Incision of the Prostate (TUIP); Transurethral Vaporization of the Prostate (TUVP); Photoselective Vaporization of the Prostate (PVP); Prostatic Urethral Lift (PUL); Transurethral Microwave Therapy (TUMT); Water Vapor Thermal Therapy; Transurethral Needle Ablation (TUNA); Laser enucleation; Aquablation; and Prostate Artery Embolization (PAE).

AUA guidelines use a 3-tiered evidence system in which the evidence level associated with a statement is classified as high (A), moderate (B), or low (C), and that recommendations without a sufficient evidence basis are labeled as a 

In his presentation, Kaplan detailed the 2020 updates, which included 1 new statement and several amended statements.

The new statement, known as “statement 6,” was added to the “Evaluation and Preoperative Testing” section of the guideline. The statement, which is categorized as a clinical principle, reads:

“Clinicians should inform patients of the possibility of treatment failure and the need for additional or secondary treatments when considering surgical and minimally-invasive treatments for LUTS secondary to BPH.”

The text for this statement was taken from supporting text on retreatment and treatment failure from the treatment modality statements.

Regarding this new statement, Kaplan said, “The text for this statement was taken from the corresponding treatment modality statements.” Some of the statements that were amended to have retreatment and/or treatment failure information moved to statement 6 included statement 15 on PUL, statement 17 on TUMT, statement 18 on water vapor thermal therapy, and statement 22 on aquablation.

The first amendment was made to statement 1, which is part of the “Evaluation and Preoperative Testing” section of the guidelines. The statement now recommends that a physical examination, along with a medical history, should be conducted as part of the initial assessment of patients with “bothersome” LUTS potentially caused by BPH (clinical principle). The AUA Symptom Index should be used, and the physician should perform a urinalysis.

Additionally, supporting text added to the statement reads, “When focusing on the results of the urinalysis, clinicians should focus on the presence or absence of glucosuria, proteinuria, hematuria, and infection.”

The wording of statement 16 on PUL (grade C) was amended to now read, “PUL may be offered to eligible patients who desire preservation of erectile and ejaculatory function.”

Although the wording of statement 19 on water vapor thermal therapy (grade C) was not changed, the supportive text was amended based on the latest literature.

The statement itself reads, “Water vapor thermal therapy may be offered to eligible patients who desire preservation of erectile and ejaculatory function.”

“In the randomized controlled trial comparing water vapor thermal therapy to sham, the original 136 patients randomized to water vapor thermal therapy are expected to be followed for 5 years. Few harms occurred in the water vapor thermal therapy group between months 3 and 12.

A decrease in ejaculatory volume was reported by 2% of participants. At 36 months, no de novo erectile dysfunction was reported but dysuria was reported by 1% of patients. At 48 months, there was a significant change in International Index of Erectile Function (IIEF) scores compared to baseline with a 

 value of .3. But there was not a significant change at the other follow-up intervals.”2

Supporting text was also updated based on new literature for statement 21 on laser enucleation (grade B), and the statement itself was also changed. Specifically, the word “suitable” was removed before the word options, so it now reads:

“Clinicians should consider holmium laser enucleation of the prostate (HoLEP) or thulium laser enucleation of the prostate (ThuLEP), depending on their expertise with either technique, as prostate size-independent options for the treatment of LUTS attributed to BPH.”

The wording of statement 23 on PAE (expert opinion) was also amended and now reads:

“PAE for the treatment of LUTS secondary to BPH is not supported by current data and trial designs, and benefit over risk remains unclear; therefore, PAE is not recommended outside the context of clinical trials.”

The AUA BPH panel is currently working on the guideline and algorithm for the medical management of BPH, which is slated to be released next year. The literature for this guideline was pulled from the date range of 2010 through 2019, with the evidence reported included 107 randomized controlled trials and controlled clinical trials.

“We will modify and evolve some of the statements from the 2020 BPH guideline and incorporate this into the 2021 guideline, and update [the information] based on the current literature. This will also include any updates in the surgical management of BPH, as well.”

1. Kaplan SA. AUA Guidelines 2020: BPH. Presented during 2020 AUA Virtual Experience. June 27-28, 2020.

2. McVary KT, Rogers T, Roehrborn CG, et al. Rezūm water vapor thermal therapy for lower urinary tract symptoms associated with benign prostatic hyperplasia: 4-year results from randomized controlled study. 

. 2019;126:171-179. doi: 10.1016/j.urology.2018.12.041.

Articles

Steven A. Kaplan, MD, explains the updates in the AUA 2020 guideline on lower urinary tract symptoms secondary to benign prostatic hyperplasia.

Panel expert details changes to AUA BPH guideline

Researchers at Memorial Sloan Kettering (MSK) Cancer Center showed that active surveillance with a well-defined monitoring plan is a safe approach for appropriate patients with low-risk prostate cancer.

In the MSK retrospective analysis of over 2600 men who received active surveillance, there were 5 men who developed distant metastasis. The investigators concluded that only 2 of these patients had cancer that immediate initial treatment might have cured. At 10 years, the risk of distant metastasis was 0.6% (95% CI, 0.2-2.0).

“We have demonstrated that active surveillance is a safe management strategy at a tertiary cancer center when patients are appropriately selected and a well-defined monitoring plan is followed, in particular for men with very low risk prostate cancer. The long-term risk of metastasis is very low. The current study confirms prior reports demonstrating a low incidence of oncologic events in men with low-risk prostate cancer on active surveillance,” first study author Sigrid Carlsson, MD, PhD, and coinvestigators wrote in their study, which was published in the 

Using the prospectively maintained database of patients with prostate cancer at MSK, the researchers identified 2907 patients who were managed with active surveillance from 2000 to 2017. The study was then focused on a subgroup of 2664 patients who had Grade Group 1 disease (Gleason score ≤6).

As part of the active surveillance approach used for the patients, the treating physicians at MSK had recommended confirmatory biopsy. Patient status was reexamined every 6 months with a review of symptoms, a PSA test, and a digital rectal examination (DRE). In more recent years, MRI was increasingly used at these follow-up visits. Repeat biopsy was done every 2 to 3 years, or following changes in MRI/DRE or a sustained increase in PSA level.

The median patient age was 62 years (range, 57-68), the median PSA at diagnosis was 5 ng/ml, the median number of positive cores at diagnosis was 1, the median total cores at diagnosis was 12, and the median nomogram risk of locally advanced disease was 35. The clinical stages at diagnosis were T1C or less (89%), T2A (9.3%), T2B (1.3%), T2C (0.9%).

The treatment-free probability was 76% (95% CI, 74-78), 64% (95% CI, 61-68) and 58% (95% CI, 51-64), at 5, 10, and 15 years, respectively. The number of men at risk for metastasis was 1146, 220, and 25 at those same 3 cutoff points, respectively.

Beyond the 10-year risk of distant metastasis of 0.6%, the risk of distant metastasis was 1.5% (95% CI, 0.4-5.2) at 15 years.

“While these rates align with those of other active surveillance cohorts and support the oncologic safety of active surveillance over longer term follow-up, we do note that the upper bound of the confidence interval at 15 years is clinically relevant (5.2% risk of metastasis). However, of the 5 patients with distant metastases, only 2 might have been cured by early treatment.”

The overall survival rate at 10 years was 94% (95% CI, 92-95). Among the 2664 men with Grade Group 1 prostate cancer, only 1 died of prostate cancer.

“Our experience confirms, on a large scale, prior reports that active surveillance is an oncologically safe strategy for men diagnosed with low risk prostate cancer. Active surveillance should be strongly recommended for such patients as it avoids treatment related morbidity without compromising cancer control,” Carlsson et al concluded.

Carlsson S, Benfante N, Alvim R, et al. Long-term outcomes of active surveillance for prostate cancer: The Memorial Sloan Kettering Cancer Center experience. 

. 2020;203:1122-1127. https://doi.org/10.1097/JU.0000000000000713

At 10 years, the risk of distant metastasis was 0.6%.

MSK study supports active surveillance for low-risk prostate cancer

Cabozantinib (Cabometyx) showed clinical activity in patients with heavily pretreated, platinum-refractory metastatic urothelial carcinoma, opening the potential to explore the multikinase inhibitor in combination regimens in this setting, according to findings from a phase 2 trial published in the 

In a cohort of patients with metastatic urothelial carcinoma, cabozantinib induced an objective response rate of 19% (95% CI, 9-34). Eight of 42 evaluable patients had responses, including 1 complete response and 7 partial responses.

“Cabozantinib has innate and adaptive immunomodulatory properties providing a rationale for combining cabozantinib with immunotherapeutic strategies,” lead study author Andrea B. Apolo, MD, medical oncologist and chief of the bladder cancer section of the Genitourinary Malignancies Branch, National Cancer Institute, and coinvestigators wrote.

There were 3 cohorts in the study: patients with metastatic urothelial carcinoma (cohort 1; n = 49), patients with bone only urothelial carcinoma metastases (cohort 2; n = 6), and patients with rare histologies of the genitourinary tract (cohort 3; n = 13). The 68 patients on the trial were enrolled between September 28, 2012, and October 20, 2015.

All patients were treated with cabozantinib at 60 mg orally once daily in 28-day cycles. Treatment was administered until disease progression or unacceptable toxicity. All trial participants were treated with at least 1 dose of cabozantinib.

Among the 57 evaluable patients across the entire study, the median follow-up time was 61.2 months (IQR, 53.8-70). Beyond the 8 responders in cohort 1, an additional 19 (45%) patients had stable disease, leading to an overall clinical benefit rate of 64% (95% CI, 48-79). The other 15 evaluable patients in cohort 1 had progressive disease.

Also in cohort 1, the median progression-free survival (PFS) was 3.7 months, the 6-month PFS rate was 37%, and the 12-month PFS rate was 10%. The median overall survival (OS) was 8.1 months, the 6-month OS rate was 64%, and the 12-month OS rate was 26%.

Three of the 5 evaluable patients in cohort 2 had a bone response per Na ¹⁸F-FDG PET/CT. In cohort 3, 5 of 10 evaluable patients with rare histologies achieved a best response of stable disease. The remainder of the evaluable patients in cohorts 2 and 3 had progressive disease.

The median PFS in cohort 2 was 5.3 months, the median OS was 9.3 months, and the 6-month OS rate was 80%. Among the patients in cohort 3, the median PFS was 2.9 months and the median OS was 5.8 months. The 6-month PFS and OS rates were 10% and 50%, respectively.

Regarding safety, the most frequently observed grade 3/4 adverse events across the study population were fatigue (n = 6), hypertension (n = 5), proteinuria (n = 4), and hypophosphatemia (n = 4). No death related to study treatment occurred.

“The clinical activity observed in this study provides a basis for further clinical investigations of cabozantinib for the treatment of metastatic urothelial carcinoma and other patient populations with rare genitourinary malignancies. Ongoing studies combining cabozantinib with immune-checkpoint inhibitors might lead to new therapeutic options for patients with advanced urothelial carcinoma and rare genitourinary malignancies,” wrote Apolo et al.

Some of the regimens being explored in these ongoing studies include cabozantinib plus nivolumab (Opdivo) with or without ipilimumab (Yervoy; NCT02496208); cabozantinib plus durvalumab (Imfinzi; NCT03824691); and cabozantinib plus atezolizumab (Tecentriq; NCT03170960).

In the genitourinary cancer treatment paradigm, cabozantinib is currently approved by the FDA as a monotherapy for the treatment of patients with advanced renal cell carcinoma.

Apolo AB, Nadal R, Tomita Y, et al. Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial [published online July 6, 2020]. 

. https://doi.org/10.1016/ S1470-2045(20)30202-3

Cabozantinib's single-agent activity opens the potential for combination approaches with immunotherapy in patients with heavily pretreated urothelial carcinoma.

Cabozantinib shows intriguing activity in heavily pretreated urothelial carcinoma

A group of researchers in Australia showed that a multianalyte liquid biopsy assay could predict which patients with metastatic castration-resistant prostate cancer (mCRPC) would likely respond to standard treatments, according to a study published in 

Using a cell-free DNA (cfDNA) and cell-free RNA (cfRNA) next-generation sequencing liquid biopsy assay, investigators demonstrated that, “Abnormalities in the androgen receptor (AR) gene detected in the blood of men with advanced prostate cancer were associated with poor responses to available drug treatments and reduced survival. This information could be used to better guide treatment of advanced prostate cancer," senior author Arun Azad, MBBS, PhD, a medical oncologist at Peter MacCallum Cancer Centre (Peter Mac) in Melbourne, Australia, stated in a press release.

The study prospectively enrolled 67 patients with mCRPC. All patients were starting treatment with either androgen receptor pathway inhibitors (ARPIs; eg, abiraterone acetate [Zytiga] or enzalutamide [Xtandi]; n = 41), or taxane-based chemotherapy (n = 26). Using the liquid biopsy assay, which is manufactured by Predicine, researchers at Peter Mac and the Monash University School of Clinical Science, in collaboration with the Chris O'Brien Lifehouse cancer treatment center, conducted integrated cfDNA and cfRNA profiling from a single 10-ml blood tube. The investigators next examined potential links between AR aberrations and clinical outcomes using Cox regression analyses and Kaplan-Meier survival estimates. 

The AR aberrations assessed included somatic mutations, copy number variation, and splice variants (AR-V7 and AR-V9). The investigators were able to successfully sequence cfRNA in 59 (88%) patients and cfDNA in all 67 patients. Overall, 36 (54%) patients had one or more AR aberrations.

AR gain was independently associated with clinical/radiographic progression-free survival (PFS; HR, 3.2, 

 = .01) and overall survival (OS; HR, 2.8; 

 = .04). Cumulative number of AR aberrations was also independently associated with PFS (HR, 3.0 for 0 vs ≥2; 

 = .04) and OS (HR, 2.9 for 0 vs ≥2, 

 = .03). The investigators also reported an association between concurrent AR gain and AR splice variant expression (AR gain/AR-V+) with shorter prostate-specific antigen PFS, regardless of whether patients received chemotherapy (HR, 3.9; 

The researchers validated their most significant results in an independent cohort of 40 patients with mCRPC. This included shorter OS in patients with AR gain/AR-V+ disease histology (HR, 3.3; 

“We demonstrate[d] the utility of a novel, multianalyte liquid biopsy assay capable of simultaneously detecting AR alterations in cfDNA and cfRNA. Concurrent profiling of cfDNA and cfRNA may provide vital insights into disease biology and resistance mechanisms in mCRPC,” the authors wrote in their conclusion.

Limitations of the study were noted as follow-up period and sample size.

"While advances in therapeutic strategies have significantly improved quantity and quality of life for men with mCRPC, there remains a pressing need to find predictive and prognostic biomarkers," Azad stated in the press release.

"Liquid biopsies have emerged as a minimally-invasive alternative to conventional biopsy for interrogating the prostate tumor genome. Liquid biopsies have demonstrated strong congruence with tumor biopsies, whilst simultaneously encapsulating the genomic complexity often seen in mCRPC," added Azad.

1. Blood test can guide treatment for most aggressive prostate cancer. Published July 7, 2020. https://bit.ly/3ecnwUs. Accessed July 8, 2020.

2. Fettkea H, Kwana EM, Docantoa MM, et al. Combined cell-free DNA and RNA profiling of the androgen receptor: clinical utility of a novel multianalyte liquid biopsy assay for metastatic prostate cancer [published online May 30, 2020]. Eur Urol. 10.1016/j.eururo.2020.03.044

Abnormalities in the androgen receptor gene detected in men with advanced prostate cancer were associated with poor responses to available drug treatments and reduced survival.

Author | Jason M. Broderick

Articles

Panel expert details changes to AUA BPH guideline

MSK study supports active surveillance for low-risk prostate cancer

Cabozantinib shows intriguing activity in heavily pretreated urothelial carcinoma

New liquid biopsy assay predicts treatment outcomes in mCRPC