Leonard G. Gomella, MD

 Editorial Council, is chairman of the department of urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia.

Since the pioneering work of Huggins and Hodges was first published nearly 80 years ago in 

 (1941; 1:293–7), the management of metastatic prostate cancer has relied on primary androgen deprivation therapy (ADT). Reducing the circulating levels of androgens is the foundation for all treatments, from newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) through the late stages of metastatic castration-resistant prostate cancer (mCRPC). While ADT usually slows prostate cancer progression, metastatic prostate cancer remains a fatal disease in need of improved therapies.

The phase III ARCHES trial evaluated enzalutamide (XTANDI) plus ADT in men with mHSPC. The study met its primary endpoint of improving radiographic progression-free survival versus ADT alone. ARCHES is another example of the trend in combining agents to improve outcomes, a concept known as “therapeutic layering.”

Enzalutamide plus ADT improves rPFS in hormone-sensitive PCa

Therapeutic layering, first described in the treatment of mCRPC, adds one or more agents onto an existing therapy 

 The concept is now becoming commonplace in the initial treatment of newly diagnosed metastatic prostate cancer.

Other recent examples of therapeutic layering in which agents are added to ADT in mHSPC include the CHAARTED trial (adding docetaxel), the LATITUDE trial (adding abiraterone [ZYTIGA]/prednisone), and the TITAN trial (adding apalutamide [Erleada]). Results from both CHAARTED and LATITUDE demonstrated improved overall survival with the combination therapy. Preliminary results from TITAN have also shown improved survival. ARCHES has shown the benefit of layering enzalutamide with ADT.

The recent trials using therapeutic layering are redefining how initial mHSPC is managed. Historically, the addition of nonsteroidal antiandrogens (eg, flutamide, bicalutamide) to ADT regimens represented the first therapeutic layering attempts, but only minor improvements in long-term outcome were seen with this combined androgen blockade (CAB) approach. CAB outcomes were inferior to those of recent trials that support the combined use of ADT with chemotherapy or next-generation androgen receptor pathway blockers in mHSPC.

Docetaxel and abiraterone are now part of mHSPC guidelines such as those from the National Comprehensive Cancer Network. With the likely approval of enzalutamide based on the ARCHES trial, we will have one more agent available to perform therapeutic layering to improve outcomes in men with newly diagnosed metastatic prostate cancer.

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"Therapeutic layering... is now becoming commonplace in the initial treatment of newly diagnosed metastatic prostate cancer," writes Leonard G. Gomella, MD.

Therapeutic layering in advanced PCa: Another win

Editorial Council, is chairman of the department of urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia.

It is well established that African-American men are more likely to develop prostate cancer and experience higher mortality than other ethnic groups. Most research has focused on determining the causes of prostate cancer in this high-risk group. Numerous studies have evaluated socioeconomic issues, participation in screening, disparities in care for early disease, lifestyle issues, dietary factors, obesity, physical activity and others to identify potential causes.

However, these studies have often been conflicting and inconclusive. While genomics and other biologic analysis are a relatively new focus of these investigations, the complex interactions among all of these factors that may cause prostate cancer remain incompletely understood.

Two provocative studies reported at the 2018 ASCO annual meeting provide additional insight into prostate cancer racial disparities in a different group of patients, namely men with advanced prostate cancer who participated in a variety of clinical trials. In a 

 of these trials by Halabi and associates, the relative risk of death was found to be 19% lower for African-American men than for Caucasian men.

 of 100 men balanced by race reported by George and associates using abiraterone acetate (ZYTIGA), progression-free survival was identical in African-American men compared with Caucasians. Surprisingly, PSA declines and the durability of this response was much greater in African-American patients. What is unique about these two studies is the investigation of racial differences in advanced prostate cancer outcomes in the era of newer therapeutic options.

These studies, both based on clinical trial participation, suggest that some African-American men with advanced disease may actually possess characteristics that make them respond better. With these two trials engaged in ongoing molecular analysis of some of their cohorts, genomic and single nucleotide polymorphism analysis should provide further insight into the optimum management and safety profiles of these advanced prostate cancer therapies.

Previous studies that have identified unique biomarkers with significant differences in expression by ethnicity suggest there may be different molecular pathways that lead to the development of prostate cancer. These differing pathways may also be found to impact response to advanced prostate cancer therapy in different races.

These two studies may not provide insight into the primary causes of the racial disparities in prostate cancer. However, they do provide hope that when treated for advanced prostate cancer, the outcomes in African-Americans appear to be at least as good, if not better, than other ethnicities.

"Two provocative studies reported at the 2018 ASCO annual meeting provide additional insight into prostate cancer racial disparities in a different group of patients, namely men with advanced prostate cancer who participated in a variety of clinical trials," writes Leonard G. Gomella, MD.

Rethinking race and prostate cancer outcomes

Health care costs are a concern. When considering the expense of prostate cancer care, this disease often takes center stage. While advanced prostate cancer care costs are significant, early low-risk prostate cancer is a common target for cost savings, as many men may not require aggressive treatment and can be spared the inconvenience and expense of side effects.

At this year’s Genitourinary Cancers Symposium, Gaylis and fellow urologists from a group in San Diego conducted a 3-year analysis of the cost of active surveillance (AS) versus active treatment (surgery or radiation) for low-risk prostate cancer. Their findings support that AS is a beneficial management strategy for low-risk prostate cancer from a cost perspective supporting consideration as a value-based care model by Medicare.

On the surface, this study validates previous modeling studies in support of substantial AS cost savings compared to active treatment. However, the data also illustrate the challenges of practice-specific cost analysis.

AS linked with cost savings in low-risk PCa

The follow-up is only 3 years and in a limited number of men (195), with approximately half undergoing AS and the rest receiving treatment, suggesting many men who received treatment were younger (not Medicare age). The average number of biopsy sessions was two per AS patient, and only six men had at least one MRI. Four men who had genomic testing drove up the cost of AS about $5,000 per patient.

While no uniform standards exist for AS, groups such as the National Comprehensive Cancer Network suggest repeat biopsy should be considered annually and that MRI and genomic assays have a role (and an expense). There is also concern that African-American men may not fare well on AS.

AS cost savings are dependent on patient age; in younger men, the savings may end at 7 years. AS uncertainties that impact cost include future surgery or radiation and biopsy-related complications. Thirty to 50% of men on AS will undergo treatment, and this is not seen in this analysis.

This presentation supports AS cost savings at 3 years. However, the study authors’ approach to AS in low-risk prostate cancer may not be representative of guidelines or other practice patterns. AS is very cost effective over the short term compared to prostatectomy and radiation, but there are a number of factors that may impact actual AS cost savings over the long term.

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"AS is very cost effective over the short term compared to prostatectomy and radiation, but there a number of factors may impact actual AS cost savings over the long term," writes Leonard G. Gomella, MD.

Author | Leonard G. Gomella, MD

Articles

Therapeutic layering in advanced PCa: Another win

Rethinking race and prostate cancer outcomes

The cost of prostate Ca care: What counts for AS?