He first reviewed the hypothalamic-pituitary – testis/adrenal axis as is relates to prostate cancer, highlighting steps in the axis where medical or surgical therapies could be employed to treat prostate cancer.
He reviewed medical approaches to treatment including:
- Androgen deprivation with orchiectomy, LHRH agonists, and antagonists
- Low potency androgen receptor antagonists (including flutamide and bicalutamide)
- High potency androgen receptor antagonists (including enzalutamide, apalutamide and darolutamide)
- Testosterone synthesis inhibitors (including ketoconazole, abiraterone and other agents which are currently investigational)
- Other miscellaneous agents including megestrol, spironolactone, estrogens, and agents targeting the glucocorticoid axis
- 5-alpha reductase inhibitors
Across all categories of systemic treatment for patients with advanced prostate cancer, he highlighted treatment-related toxicity including cost, fatigue, neuropsychiatric effects, sexual dysfunction, bone-health issues, sarcopenia, frailty, and metabolic syndrome.
He then discussed the clinical heterogeneity of the castrate sensitive disease state as highlighted in the figure below:
Many of these sub-states are defined based on relatively arbitrary criteria. Biochemical recurrence following local therapy is clearly arbitrary with a threshold of 0.2 ng/mL employed among patients who underwent surgery and the ASTRO or Phoenix definitions used for patients who underwent radiotherapy. The presence or absence of metastatic disease in this patients was more a reflection of our technological ability to identify these lesions, rather than underlying tumor biology, in Dr. Stadler’s view. Further, categorizations of the burden of metastatic disease, while based on an underlying prognostic rationale, are relatively arbitrary too. Finally, PSA velocity, a continuous variable, is routinely categorized to all for simpler use by clinicians.
Among patients with advanced disease (pT3 or N+ following surgery) and those with a slow biochemical recurrence following local therapy, he advocated a conservation approach. This is supported by the Pound data which found approximately 7 year delay from biochemical recurrence to metastasis in these patients. Interesting, in the EORTC 30891 trial which randomized to early versus delayed ADT in patients with untreated local disease, survival benefits were seen to early therapy in overall but not prostate cancer-specific survival.
Among these same patients, as well as those with a rapidly rising PSA without radiographic metastatic and among patients who had locally advanced, node positive, or minimal burden of metastatic disease with the prostate in situ, he recommended consideration of focal radiotherapy, potentially with ADT and/or more advanced androgen blockade.
Among patients which a rapidly rising PSA following local therapy and among any patient with advanced disease who had not received local therapy, he recommended androgen deprivation therapy plus androgen receptor targeting. The question of which agent to use (abiraterone and docetaxel are both supported by phase 3 RCTs and guidelines while the data supporting enzalutamide in this space are due to be presented at the upcoming ASCO meeting in June), was somewhat unclear. Further, there are numerous ongoing trials seeking to assess the value of combining these agents, based on the principle, as Dr. Stadler stated it, that “if a little is good, more is better”. These trials will assess the value of combining abiraterone and enzalutamide together with ADT; combining abiraterone and transdermal estrogen together with ADT; and combining ADT, abiraterone, and apalutamide.
He concluded by pointing out that prostate cancer remains an androgen receptor-driven cancer. Thus, castration is the first line therapy. Second generation AR-targeting agents are definitively indicated for patients with metastatic castrate sensitive disease. Their value in patients with locally advanced disease, in patients undergoing salvage therapy, and in biochemically recurrence disease remain under assessment. Combining androgen synthesis inhibitors with AR-antagonists is still under investigation.
Presented by: Walter Stadler, MD, Fred C. Buffett Professor of Medicine and Surgery, Chief, Section of Hematology/Oncology, Director, Genitourinary Oncology Program, Deputy Director, Comprehensive Cancer Center, The University of Chicago
Written by: Christopher J.D. Wallis, Urology Resident, University of Toronto, @WallisCJD on Twitter at the American Urological Association's 2019 Annual Meeting (AUA 2019), May 3 – 6, 2019 in Chicago, Illinois