ESMO 2023: Tolerance and Long-Term Side-Effects

(UroToday.com) The 2023 European Society of Medical Oncology (ESMO) Annual Congress held in Madrid, Spain between October 20^th and 24^th, 2023 was host to a ‘Dissecting metastatic castration-sensitive prostate cancer (mCSPC) for optimal patient benefit’ session. Dr. Alicia Morgans discussed the tolerance and long-term side effects of medical treatment of patients in the mCSPC disease space.

Dr. Morgans noted that ‘testosterone suppression’ is more than just lowering testosterone levels. Hormonal therapy for prostate cancer lowers both testosterone and estrogen levels, given that testosterone undergoes peripheral aromatization to estrogen.

An important issue to consider with ADT administration and side effects/adverse events is that the proportion of men exposed to ADT increases with age. A US population-based analysis demonstrated that this figure increases from 41% of men ages 65 – 69 to 60% of those over 80 years of age.¹

But how do these treatments affect patient quality of life? Patient reported outcomes from LATITUDE demonstrated that the addition of abiraterone to ADT, as compared to ADT alone, was actually associated with improvements in patient-reported outcomes, assessed using the FACT-P questionnaire. Thus, it is not a foregone conclusion that treatment intensification comes at the cost of worse quality of life outcomes but may actually serve a dual purpose in addition to cancer control.

Analogous analysis from TITAN demonstrated that the addition of apalutamide to ADT was associated with similar quality of life outcomes (FACT-P), compared to patients receiving ADT alone.³ While not improving patient-reported outcomes as with abiraterone in LATITUDE, this at least confirms that quality of life is at least as good with the addition of an ARPI.

What about quality of life when ARPIs are compared to other agents, such as docetaxel? Analysis from the STAMPEDE platform demonstrated that quality of life appears to be better for mCSPC patients treated with abiraterone compared to docetaxel. We note that the global quality of life initially suffers with docetaxel, but by four years follow-up, ‘catches up’ to abiraterone, albeit still slightly worse.

What about triplet therapy? ENZAMET, which included 45% who received or were planned for docetaxel, demonstrated that the addition of enzalutamide, versus a non-steroidal anti-androgen, was associated with stable, non-inferior health-related quality of life outcomes. Deterioration-free survival, a composite outcome combining oncologic and health-related quality of life outcomes, suggests that this may be improved with the addition of enzalutamide to ADT + docetaxel in mCSPC patients.

Analysis of the ARASENS trial demonstrated that the addition of darolutamide to ADT+ docetaxel prolongs the time to worsening of prostate cancer-related quality of life (HR: 0.63, 95% CI: 0.39 – 1.04). This however does not assess the incremental quality of life benefits/harms of adding docetaxel to ADT + darolutamide.

Based on this data, Dr. Morgans concluded that ADT + ARPI can be well-tolerated by most patients and may improve quality of life versus ADT alone. Conversely, docetaxel can be tolerated by many patients with supportive management, although there appears to be an initial (~4 years) decrease in quality of life.

In addition to quality of life, we need to consider the short and long-term treatment implications in this setting. Ischemic heart disease remains the leading cause of mortality worldwide, and ADT affects cardiac risk factors, which include:

• Increasing total cholesterol
• Increasing triglycerides
• Increasing abdominal adipose tissue
• Decreasing insulin sensitivity

Another complicating issue is that a significant proportion of these patients have either pre-existing cardiovascular disease or significant associated risk factors. The RADICAL-PC study of 2,811 Canadian prostate cancer patients demonstrated that 23% had pre-existing cardiovascular disease. Furthermore, half of them had at least 3 of 5 risk factors that were deemed poorly controlled. Of these risk factors, frailty was associated with the highest risk of poor cardiovascular outcomes.⁴

Further evidence of this accord comes from the HERO trial of relugolix (oral GnRH antagonist). 93% of patients in the overall cohort had cardiovascular, with 14% having a history of a major acute cardiac event. Notably, many of these risk factors are modifiable lifestyle risk factors (67%), which highlights the potential for additional physician-led and other efforts to maximize cardiovascular outcomes in this vulnerable population.

The importance of this is highlighted by data from D’Amico et al that demonstrated that the overall mortality is worse when ADT is added to radiotherapy for patients with moderate to severe comorbidity, but not those with none or minimal comorbidity, which suggests that ADT has a selectively worse adverse event profile in unhealthier patients, re-emphasizing the importance of targeting modifiable risk factors.

Are there any drugs that have a more favorable cardiovascular event profile? GnRH antagonists may be associated with lower risks of cardiovascular disease. In the phase III hero trial, the oral GnRH antagonist relugolix was associated with a 54% reduction in the risk of major cardiovascular events compared to leuprolide. This benefit appears to be most significant in patients with a prior cardiac disease history with 5.8-fold decrease in the odds of a cardiac event, compared to 1.5 in those without such a history.⁶

The PRONOUNCE randomized controlled trial aimed to compare the cardiovascular safety of degarelix versus leuprolide in prostate cancer patients. While this study did not demonstrate any differences in cardiovascular events between the treatment arms,^7,8 and is an important addition to the literature, no definitive conclusions are possible for the following reasons:

• This trial enrolled only half of the intended target size over a long period, which limited the study's power to assess for differences
• There was a strong engagement from treating cardiologists to optimize modifiable risk factors and medically reduce the risk of cardiovascular disease in both arms, which does not commonly occur in routine clinical practice.

What about ARPIs? It appears that both abiraterone and enzalutamide increase the rate of hospitalizations or all-cause mortality in patients with 3 or more cardiovascular disease comorbidities.

The NCCN guidelines currently recommend the ‘ABCDE’ systematic approach to addressing cardiovascular risk factors in cancer patients, summarized below:

What about ADT and subsequent fragility fractures? 20 to 25% of hip fractures occur in men worldwide, with mortality two-fold higher for men than women during the initial 6 months post-fracture. Hip fractures cause loss of mobility, loss of independence, and create a significant financial burden. As such, the importance of this matter in this patient cohort becomes clear.

It has long been established that ADT increases the risk of bone fractures:

How do we address this? Guidance to this accord comes from the ESMO which recommends that denosumab (twice yearly) or bisphosphonates (once yearly) be used in patients with any 2 risk factors, including:

• Age >65 years
• T score < -1.5
• History of or current smoking
• BMI <24
• Family history of hip fracture
• Personal history of fragility fracture above age 50
• Oral glucocorticoid use for >6 months

Another known side effect of ADT is the increased associated risk of depression. In a population-based study of 78,552 men with prostate cancer, of whom 43% were treated with ADT, the use of ADT was associated with a 23% relative increased hazard of depression.⁹

Additionally, given that testosterone crosses the blood-brain barrier and acts on androgen receptors in the hippocampus and amygdala, this plays an important role in learning, memory, and prevention of cognitive decline, with low levels of testosterone associated with worsening of visual and verbal memory. This is reflected in the increased incidence of Alzheimer’s disease in claims-based data of men receiving ADT.

Gonzalez et al. demonstrated that this increased risk of cognitive impairment may be selectively worsened by ADT in patients with specific single nucleotide polymorphisms. Patients with the wild type rs1047776 genotype have 14-fold increased odds of impaired cognitive performance with ADT, whereas those with the 1+ abnormal allele had a risk similar to those that did not receive ADT.¹⁰

When we aggregate all the complications of ADT, it becomes clear that we induce a ‘frailty’ state in our patients. As such, it becomes incumbent on us to take additional measures to help mitigate reversible risk factors in this vulnerable population.

Additional means of reducing ADT-related toxicity is to limit the patient’s exposure to these drugs, particularly among responders. A DREAM study is evaluating this in mCSPC patients on ADT + an ARPI who established a PSA <0.2 ng/ml following 18-24 months of ADT.

Dr. Morgans concluded that:

• Intensified treatment for mHSPC is well tolerated by most patients, with several studies suggesting improved quality of life with intensification.
• Survivors living with or after hormonal therapies are at risk for cardiac, metabolic, skeletal, mood, and cognitive complications, among many other effects.
• The constellation of effects is similar to the frailty phenotype defined in the geriatric literature.
• Current strategies engaging multi-disciplinary teams can reduce morbidity and mortality and ensure that patients live well during their treatment for mCSPC.

1. Gilber SM, Kuo Y, Shahinian VB, et al. Prevalent and incident use of androgen deprivation therapy among men with prostate cancer in the United States. Urol Oncol. 2011; 29(6):647-653.
2. Chi KN, Protheroe A, Rodriguez-Antolin A, et al. Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial. Lancet Oncol. 2018; 19(2):194-206.
3. Agarwal N, McQuarrie K, Bjartell A, et al. Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cancer (TITAN): a randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2019; 20(11):1518-1530.
4. Leong DP, Fradet V, Sahyegan B, et al. Cardiovascular Risk in Men with Prostate Cancer: Insights from the RADICAL PC Study. J Urol. 2020; 203(6):1109-1116.
5. D’Amico AV, Chen M, Renshaw A, et al. Long-term Follow-up of a Randomized Trial of Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer. JAMA. 2015;314(12):1291-3.
6. Shore ND, Saad F, Cookson MS, et al. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med. 2020 ;382(23):2187-2196.
7. Lopes RD, Higano CS, Slovin SF, et al. Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Prostate Cancer: The Primary Results of the PRONOUNCE Randomized Trial. Circulation. 2021; 144(16):1295-1307.
8. Melloni C, Slovin SF, Blemings A, et al. Cardiovascular Safety of Degarelix Versus Leuprolide for Advanced Prostate Cancer: The PRONOUNCE Trial Study Design. J Am Coll Cardiol CardioOnc. 2020; 2(1):70-81.
9. Dinh KT, Reznor G, Muralidhar V, et al. Association of Androgen Deprivation Therapy With Depression in Localized Prostate Cancer. J Clin Oncol. 2016; 34(16):1905-1912.
10. Gonzalez BD, Lim HSL, Booth-Jones M, et al. Course and Predictors of Cognitive Function in Patients With Prostate Cancer Receiving Androgen-Deprivation Therapy: A Controlled Comparison. J Clin Oncol. 2015; 33(18):2021-7.