Based on the recently published ENZAMET, ARCHES, and TITAN trials,1-3 we now have several choices of systemic combination therapies for men with metastatic hormone-sensitive prostate cancer. Today, men are faced with decisions of androgen-deprivation therapy alone or combinations with abiraterone, docetaxel, enzalutamide, or apalutamide, and there are now additional complex decisions around triple combination or sequential therapy with induction androgen-deprivation therapy/docetaxel plus a potent androgen-receptor inhibitor or whether single-agent chemotherapy or androgen-receptor inhibitor use with androgen-deprivation therapy is sufficient. These decisions are presently based on costs, availability and approvals, disease risk/volume, patient age and comorbidity, and of course shared decision-making.
Andrew J. Armstrong, MD, ScM, FACP
In addition, recent data support the use of radiation to the primary site for men with low-volume or oligometastatic disease, based on the STAMPEDE trial demonstrating a survival benefit for these men (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.52–0.90) but not for those with high-volume disease (HR = 1.07, 95% CI = 0.9–1.28).4 Thus, patient selection can be based on low metastatic disease burden, defined by the absence of visceral metastases and oligometastatic disease on conventional imaging (up to four sites in bone, no liver or lung metastases on computed tomography/magnetic resonance imaging or bone scan). How to handle these decisions in the face of novel, more sensitive imaging such as prostate cancer–specific positron-emission tomography tracers like prostate-specific membrane antigen, sodium fluoride, choline, or fluciclovine remains an open question. Radiation is typically integrated into care after 3 to 6 months of androgen-deprivation therapy, and we await further phase III data for radiation in the context of novel androgen-receptor therapies.
Complexity of Treatment Decisions
The decisionto pursue chemohormonal therapy vs more intensive combined androgen receptor–targeted therapy (highly active androgen-receptor therapy) is complex, given the similar efficacy outcomes in cross-trial comparisons but differences in distinct toxicities and costs. Docetaxel is likely the more cost-effective and efficient approach with androgen-deprivation therapy for men with high-volume metastatic hormone-sensitive prostate cancer; it is completed in 18 weeks with reversible—but more intense—short-term chemotherapy toxicities, is now generic and available worldwide, and is less expensive than other options. However, men with low-volume disease do not have a clear benefit from docetaxel in this setting,5 many men with high-volume disease would prefer not to receive chemotherapy and its toxicities, and some men with high-volume disease might benefit from triple therapy with androgen-deprivation therapy, docetaxel, and an androgen-receptor inhibitor, which may further delay symptomatic and radiographic disease progression or death.
In ENZAMET and the global phase III ARCHES trial, there are clear benefits overall with enzalutamide/androgen-deprivation therapy over androgen-deprivation therapy alone. There are also clearly significant improvements in overall survival, delays in clinical disease progression and radiographic progression-free survival, time to symptomatic skeletal events, and time to the need for further systemic therapy with enzalutamide use early. These results are similar with apalutamide in the TITAN trial.
The recent report from ENZAMET showed a significant overall survival benefit among all patients on interim analysis for the enzalutamide group vs the standard-care group (HR = 0.67, P = .002). However, for the subset of men with high-volume metastatic hormone-sensitive prostate cancer treated with androgen-deprivation therapy/docetaxel, overall survival data in ENZAMET, TITAN, and ARCHES remain immature. In 2019, there is no clear overall survival benefit from docetaxel plus enzalutamide (HR = 0.90, 95% CI = 0.62–1.31) or apalutamide (HR = 1.27, 95% CI = 0.52–3.09), although these confidence intervals are wide and do not exclude a clinically meaningful survival benefit. This result is despite clear significant benefits in delaying radiographic progression-free survival and clinical disease progression beyond docetaxel with both enzalutamide (HR = 0.48, 95% CI = 0.37–0.62, in ENZAMET; HR = 0.52, 95% CI = 0.30–0.89, in ARCHES) and apalutamide (HR = 0.47, 95% CI = 0.22–1.01), as well as major improvements in all secondary response and time to event efficacy endpoints regardless of prior docetaxel use.
However, the number of patients treated with docetaxel/androgen-deprivation therapy in these trials varied, ranging from 10% in TITAN and 18% in ARCHES to 45% in ENZAMET, and the decisions to receive docetaxel were determined by the provider, not the trial, and did not always correlate with volume or risk. Higher-risk, poorer-prognosis patients tended to receive docetaxel, but there is significant heterogeneity in the use of docetaxel, which could bias these subgroup analyses.
In addition, follow-up remains limited at 34 months in
ENZAMET, 22 months in TITAN, and 14.4 months in ARCHES, thus restricting the power to look at these subgroups by prior docetaxel use and disease volume. Only further follow-up and meta-analyses, as well as results from the darolutamide with docetaxel trial in this patient population (ARASENS, ClinicalTrials.gov identifier NCT02799602), can address these questions. However, a clear conclusion is that although survival may not be further prolonged with triple therapy in men with metastatic hormone-sensitive prostate cancer, delays in clinical and radiographic disease progression remain a direct clinical benefit to patients that will encourage consideration of the sequential use of docetaxel/androgen-deprivation therapy and enzalutamide or apalutamide. The concurrent use of enzalutamide and docetaxel led to increased neurotoxicity in ENZAMET, which was not observed with sequential use as in the ARCHES regimen of androgen-deprivation therapy/docetaxel followed by androgen-deprivation therapy/enzalutamide, suggesting sequential use should be preferred over concurrent use.
What About Androgen-Deprivation Therapy Alone?
Finally, there remain subsets of patients who may do well with androgen-deprivation therapy alone, even intermittently, often for decades. For example, men older than age 70 with significant comorbidities and men who achieve a prostate-specific antigen (PSA) level less than 0.2 ng/ mL on androgen-deprivation therapy alone may have a reduced benefit and increased toxicities with more potent therapy.6 In counterpoint, however, in these phase III trials, men with low-volume disease, prior local therapy, nodal vs bone vs visceral metastases, and high- or low-grade tumors all had significant improvements in survival with more potent androgen-receptor inhibition with androgen-deprivation therapy.
These data suggest the standard of care for most men with metastatic hormone-sensitive prostate cancer should not be androgen-deprivation therapy alone but rather androgen-deprivation therapy with either docetaxel or a potent androgen-receptor inhibitor as well as radiation to the primary tumor in patients with low-volume disease. Future trials of stereotactic body radiation therapy to involved metastatic sites (STAMPEDE), risk-adapted therapy based on PSA nadir on androgen-deprivation therapy (based on data from CHAARTED),6 and intermittent therapy7 in select men may clarify whether some men can safely forgo more intensive long-term androgen-receptor inhibitor therapy.
Selecting Treatments Based on More Than Efficacy Alone
Enzalutamide/androgen-deprivation therapy can now be considered a standard-of-care therapy for men with metastatic hormone-sensitive prostate cancer, with clear survival benefits over androgen-deprivation therapy alone; it offers an alternative to either standard docetaxel or abiraterone with prednisone. Apalutamide/ androgen-deprivation therapy provides a similar excellent alternative. Choices between these agents and whether to combine docetaxel or radiation to the primary with androgen-receptor inhibition should not be based on efficacy across trials alone, given their similar benefits. There are unique differences in toxicities among these agents, with abiraterone requiring prednisone and being associated with mineralocorticoid excess, enzalutamide having fatigue and fall risks particularly in older men, and apalutamide having rash. All men face a higher risk of hypertension, mild cardiovascular risk, muscle loss, fatigue, and fracture from these agents, and attention to exercise, cardiac risk reduction, and bone health and monitoring is critical. These individual decisions should center on shared individualized decision-making based on comorbidity, costs to society and individual patients, patient preference, the desire to avoid chemotherapy side effects, and the volume/burden of metastatic disease.
Dr. Armstrong is Professor of Medicine and Director of Research of the Duke Cancer Institute’s Center for Prostate and Urologic Cancers, Duke University, Durham, North Carolina.
DISCLOSURE: Dr. Armstrong has received honoraria from Dendreon, Janssen Oncology, and Sanofi; has served as a consultant or advisor to Astellas Scientific and Medical Affairs, AstraZeneca, Bayer, Clovis Oncology, Dendreon, Janssen Biotech, Medivation, Pfizer, and Sanofi; has served on the speakers bureau for Bayer, Dendreon, and Sanofi; has received institutional research funding from Active Biotech, Astellas Pharma, Bayer, Bristol Myers Squibb, Dendreon, Gilead Sciences, Janssen Oncology, Medivation, Novartis, Pfizer, Roche/Genentech, and Sanofi; received royalties or holds an institutional patent or other intellectual property for “circulating tumor cell novel capture technology”; and has been reimbursed for travel, accommodations, or other expenses by Astellas Scientific and Medical Affairs, Bayer, Dendreon, and Janssen Biotech.
REFERENCES
1. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al: ARCHES: A randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol 37:2974-2986, 2019.
2. Chi KN, Agarwal N, Bjartell A, et al: Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med 381:13-24, 2019.
3. Davis ID, Martin AJ, Stockler MR, et al: Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med 381:121-131, 2019.
4. Parker CC, James ND, Brawley CD, et al: Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): A randomised controlled phase 3 trial. Lancet 392:2353-2366, 2018.
5. Kyriakopoulos CE, Chen YH, Carducci MA, et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: Long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol 36:1080-1087, 2018.
6. Harshman LC, Chen YH, Liu G, et al: Seven-month prostate-specific antigen is prognostic in metastatic hormone-sensitive prostate cancer treated with androgen deprivation with or without docetaxel. J Clin Oncol 36:376-382, 2018.
7. Hussain M, Tangen CM, Berry DL, et al: Intermittent vs continuous androgen deprivation in prostate cancer. N Engl J Med 368:1314-1325, 2013.
