(UroToday.com) In a plenary session entitled “Advances in Prostate Cancer: Androgen Deprivation Therapy Across the Disease Continuum” held in conjunction with the American Urologic Association Annual Meeting, Dr. Daniel Lin explored the question of defining castration sensitivity in advanced prostate cancer.
Dr. Lin began by discussing key considerations in our approach to administering androgen deprivation therapy, namely choosing between GnRH agonists or antagonists. These include potential differences in efficacy, safety, and administration. He first presented early data from Dr. Klotz showing that degarelix was associated with much earlier castration than leuprolide, though rates of treatment-related adverse events were similar.
Subsequently, the HERO study compared the oral agent relugolix to leuprolide. Again, there was an earlier suppression of testosterone levels and superior sustained castration with the GnRH antagonist. Additionally, among those with a history of cardiac events, Dr. Lin highlighted data from the HERO publications showing lower rates of major adverse cardiac events among those patients receiving relugolix.
Dr. Lin then transitioned to discussing nmCRPC, emphasizing that this disease space encompasses patients with a rising PSA on ADT who have castrate testosterone levels and no radiographic evidence of metastasis on conventional imaging with bone scan and CT scan. Most of these patients will have received local therapy previously but this is not required in the definition. Further, he emphasized that these patients may have evidence of distant disease when next-generation imaging is used.
Citing the classic data from Dr. Smith and colleagues, Dr. Lin emphasized that nmCRPC is associated with a median time to metastasis of 29.5 months and median overall survival of 44.8 months. Thus, this represents a high-risk population. However, it may be further sub-divided as PSA doubling time further risk stratifies this group: those with PSA doubling times less than 6 months have a particularly poor prognosis. In particular, a shorter PSA doubling time is associated with a shorter time to metastasis. Among those with PSA doubling time less than 10 months, the risk of bone metastasis is 12x higher and the risk of death is 4x higher than those with doubling times greater than 10 months.
He further emphasized that this disease space represents a wide variety of patients based on imaging approaches. While many may rapidly progress to metastasis, some never will. Further, the effect of next-generation imaging will further change the definition of this disease space. Among patients with high-risk nmCRPC based on conventional imaging, 98% have evidence of disease based on PSMA-PET/CT: 44% of these patients have disease restricted to the pelvis while the remainder has distant metastatic disease, with a relatively large proportion harbouring polymetastatic disease. Dr. Lin then discussed the various PET tracers available highlighting that, while fluciclovine is widely available, PSMA-PET is more sensitive and specific.
Dr. Lin then transitioned to defining metastatic hormone-sensitive prostate cancer (mHSPC). This disease space includes patients with metastatic disease who are still responsive to ADT. Thus, they don’t necessarily have to be hormone naïve. Citing data from SWOG 9346, he emphasized that the PSA nadir following induction ADT is strongly associated with overall survival.
Metastatic HSPC may be further sub-divided based on disease burden, which has significant implications for treatment. High-volume disease is defined as ≥4 bone metastases and/or visceral metastases or ≥1 metastasis beyond the pelvis or vertebral column.
He then cited data from HORRAD and STAMPEDE arm H examining the role of local therapy in mHSPC. While both of these studies were negative overall, subgroup analyses have suggested a benefit among patients with low-volume disease. Further ongoing studies, including SWOG 1802 and PEACE-1 are assessing this question as well. The schemas of these two studies are presented below:
Dr. Lin then emphasized that genetic testing the standard of care for all men with metastatic prostate cancer, to look for both germ line and somatic mutations. These may have important therapeutic implications, including the identification of DNA repair defects that would sensitize to PARP inhibition or microsatellite instability/dMMR which would make a patient eligible for pembrolizumab.
Presented by: Dan Lin, MD, Chief of Urologic Oncology at the University of Washington's Department of Urology David Penson, Vanderbilt University Medical Center
Written by: Christopher J.D. Wallis, University of Toronto Twitter: @WallisCJD during the 2021 American Urological Association, (AUA) Annual Meeting, Fri, Sep 10, 2021 – Mon, Sep 13, 2021.