Dr. Graff notes that there are well-known toxicities for androgen deprivation therapy (ADT) monotherapy including cognitive decline, cardiovascular disease, bone thinning, weight gain, loss of libido, and mood changes. Additional therapies added to ADT have induced new toxicities, which may include amplification of ADT toxicities, thyroid dysfunction, rash, neuropathy, cytopenia, and financial toxicity. The following chart demonstrates treatment effect by disease state, but also the median exposure for these therapeutic treatment options:
There are treatment decisions that must be taken into consideration. For localized disease, the patient’s risk group and life expectancy; for biochemically recurrent disease, the patient’s PSA doubling time and treatment preference; for metastatic disease, treating the patient but deciding how much/aggressive to treat. GnRH agonists have been associated with coronary heart disease (aHR 1.16, p<0.001), myocardial infarction (aHR 1.11, p=0.03), and sudden cardiac death (aHR 1.16, p=0.004),1 leading to an FDA warning in 2010.
But are GnRH antagonists safer? Dr. Margel’s study assessing cardiovascular morbidity in a randomized trial comparing GnRH-agonist and antagonist among patients with advanced prostate cancer found that among men with a history of cardiovascular disease 20% of patients randomized to GnRH-agonists had a major cardiovascular and cerebrovascular event compared to 3% randomized to antagonists (log-rank p = 0.013). Dr. Graff notes that the PRONOUNCE study will test degarelix vs leuprolide in 900 men with predefined cardiac disease. The primary endpoint will be time from randomization to first confirmed occurrence of a major cardiovascular event (death from any cause, non-fatal myocardial infarction, or non-fatal stroke) up to 336 days. Furthermore, Dr. Margel is also collaborating to understand how FSH contributes and will perform large-scale proteomic analyses.
Among men with biochemical recurrence after radical prostatectomy, previous studies from Johns Hopkins Hospital suggest that prostate-specific antigen (PSA) doubling time, time to recurrence and Gleason grade are all predictive of prostate-cancer specific mortality,2 thus potentially guiding when/if we should start ADT in high-risk patients. The work presented today by Dr. Marshall and colleagues is a continuation of the Hopkins experience. In this study, they found the median metastasis-free survival (MFS) was 21 years (IQR 20-24) and median overall survival (OS) was 22 years (IQR 21-23). Among men with PSA doubling time <=6 months (n=283), the median MFS was 9 years (IQR 8-10) and median OS was 13 years (IQR 11-15). Among men who developed metastasis (n=489), the median MFS was 10 years (IQR 9-11) and median OS was 15 years (IQR 14-17). Among men who developed metastasis and had a PSA doubling time <=6 months (n=172), the median MFS was 6 years (IQR 6-8) and median OS was 10 years (IQR 9-12). Furthermore, in multivariable models, age (HR 1.06, 95% CI 1.04-1.1), Gleason < 8 vs ≥8 (HR 0.4, 95% CI 0.3-0.5), radical prostatectomy stage (organ confined vs not HR 0.6, 95% CI 0.5-0.8), PSA doubling time (HR 0.995, 95% CI 0.993-0.997) and salvage radiation therapy (HR 0.88, 95% CI 0.81-0.96) were associated with OS. Dr. Graff notes that these MFS rates are comparable to published studies, but states that these results may not be comparable considering that all patients in the Hopkins study previously underwent a radical prostatectomy.
Toxicity profiles for patients choosing chemotherapy regimens for mCRPC differ by agent. Side effects for patients treated with docetaxel may include peripheral neuropathy, stomatitis, peripheral edema, alopecia or nail disorders. Side effects for patients treated with cabazitaxel may include febrile neutropenia, neutropenic infection, diarrhea or hematuria. In the patient preference assessment of the CABADOC trial, Dr. Baciarello and colleagues found that after adjusting for the treatment period effect, more patients preferred cabazitaxel (43%) vs docetaxel (27%) (p < 0.004), whereas 30% had no preference between taxanes. Dr. Graff notes that currently patients must have docetaxel prior to cabazitaxel. However, for those who received docetaxel for mHSPC, it may be reasonable to go to cabazitaxel upon progression to mCRPC.
Dr. Graff concluded with several summary points and future directions:
- Thorough counseling of patients about their risks is important, particularly as they live longer and get more treatment
- Given that there are more treatment options than ever before, the physician-patient relationship and shared-decision making are important
- We must carefully select treatment and study long-term toxicities
Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA
References:
- Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006;24(27):4448-4456.
- Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA 2005;294(4):433-439.