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Assistant Professor of Medicine
Department of Medicine
Harvard Medical School
Lank Center for Genitourinary Oncology
Dana-Farber Cancer Institute
Atish Choudhury, MD, PhD, has disclosed that he has received consulting fees from Astellas, AstraZeneca, Bayer, Blue Earth, and Lilly.
Management of Castration-Sensitive Prostate Cancer
In the frontline management of patients with high‑risk, localized castration-sensitive prostate cancer (CSPC), biochemically recurrent CSPC, or metastatic CSPC (mCSPC), androgen-deprivation therapy (ADT) plays a critical role. ADT refers to lowering the testosterone level in a patient’s blood to castrate levels. In these disease settings, a repertoire of testosterone-lowering agents is available from which to choose. Blood testosterone levels can be lowered by surgical castration, with gonadotropin-releasing hormone (GnRH) agonists, with GnRH antagonists, or via the administration of exogenous estrogens. GnRH agonists mimic GnRH, and they act by initially overstimulating the GnRH receptor, thereby causing an initial surge in luteinizing hormone (LH) and testosterone levels. With chronic administration, GnRH agonists suppress LH and testosterone production. GnRH agonists are associated with hot flushes, erectile dysfunction, osteoporosis, loss of muscle mass, and cardiovascular events. The phase II/III PATCH trial compared exogenous estrogen given as transdermal patches with GnRH agonists and showed that exogenous estrogen is associated with a decreased risk of hot flushes and osteoporosis but higher rates of gynecomastia. As a result, transdermal estradiol is not commonly used in the United States, despite it being associated with fewer hot flushes compared with GnRH agonists. GnRH agonists or antagonists are preferred to exogenous estrogens in the United States.
Unlike GnRH agonists, GnRH antagonists cause the immediate suppression of LH and testosterone. The 2 commonly used GnRH antagonists are degarelix, which is an injection given subcutaneously every month, and the newer agent, relugolix, which is given orally daily. In the phase III HERO trial, oral relugolix demonstrated superiority regarding testosterone suppression to castrate levels in 96.7% of men vs 88.8% with leuprolide. Also, the rate of testosterone recovery after treatment discontinuation was more rapid with relugolix vs leuprolide. Although the adverse event profile of relugolix is generally similar to that reported with all other ADTs, relugolix was associated with a lower rate of major adverse cardiovascular events compared with leuprolide (2.9% vs 6.2%). In my practice, I recommend relugolix over leuprolide for my patients with a history of major cardiovascular events. A caveat to the use of relugolix, however, is the requirement for daily oral administration and the challenges with patient adherence and out-of-pocket costs, as it may be less convenient for some patients than less frequently administered leuprolide depot doses.
One of the main mechanisms of castration resistance in advanced prostate cancer is the development of gene amplification or mutations in the androgen receptor (AR), whereby AR can be activated by other hormones in the absence of androgens or in the presence of low circulating testosterone to promote prostate cancer cell growth and proliferation. To circumvent castration resistance, more potent AR pathway inhibitors were developed. The CYP17 inhibitor, abiraterone, inhibits androgen biosynthesis in the testicular, adrenal, and prostatic tumor tissues. There are also direct antagonists of AR that inhibit its transcriptional activity. The first-generation AR antagonists flutamide, bicalutamide, and nilutamide competitively bind to the ligand-binding domain of AR. The second-generation AR antagonists enzalutamide, apalutamide, and darolutamide have stronger binding affinities for AR and, in addition, block AR translocation into the nucleus. Even in the hormone-sensitive space, augmenting testosterone suppression with more potent agents that block hormone signaling or with the addition of docetaxel chemotherapy can provide additional treatment benefit compared with testosterone lowering alone.
There is no strong evidence that one of these strategies is better than the others in terms of improving clinical outcomes for patients with advanced CSPC, and these agents have different adverse event profiles. Docetaxel is associated with fatigue, myelosuppression, neuropathy, skin/nail changes, nausea/vomiting, and bowel disturbances. As such, docetaxel is not favored for frail patients. Abiraterone is associated with symptoms of mineralocorticoid excess, including hypokalemia, leg edema, and hypertension. Therefore, coadministration with prednisone is required to minimize these adverse events. The most concerning potential long‑term complications associated with abiraterone are cardiac-related events. The second-generation AR antagonists are more commonly associated with fatigue. In particular, enzalutamide and apalutamide, which are both approved by the FDA for mCSPC, seem to be associated with some cognitive dulling, an increased risk of fractures and falls, and rare risk of seizure. In the mCSPC setting, I tend to favor the FDA-approved, second-generation AR antagonists over abiraterone in patients with uncontrolled hypertension, with uncontrolled diabetes, with a recent major cardiovascular event or with significant rhythm disturbance. Of note, abiraterone can be safely administered in most of the other patient populations. However, if a patient has gait instability, cognitive dysfunction, or predisposing factors for seizure at baseline, I shy away from the AR antagonists, enzalutamide, and apalutamide. Taken together, when considering any of these agents for patients with mCSPC, the treatment choice really depends on patient preferences, preexisting comorbidities and patient expectations regarding adverse events and quality of life.
ADT alone should be considered only in a small subset of patients with severe comorbidities or those with a relatively short life expectancy, where the risk of treatment intensification is felt to outweigh the potential benefits. Relugolix has not yet been compared with leuprolide in combination with docetaxel, abiraterone, enzalutamide, or apalutamide for patients with mCSPC to know whether this agent would lead to a decreased risk of major cardiovascular events in this setting. For patients with mCSPC and cardiovascular risk factors, the results from an ongoing phase I trial will provide more insights into the safety and tolerability of relugolix when used in combination with other agents such as abiraterone, apalutamide, or docetaxel with or without prednisone (NCT04666129).
A novel treatment strategy for patients with mCSPC is docetaxel-containing “triplet therapy,” which also includes ADT and a potent AR pathway inhibitor. At the 2022 Genitourinary Cancers Symposium, data from the randomized phase III ARASENS trial were presented. ARASENS compared the safety and efficacy of ADT and docetaxel with or without darolutamide for patients with newly diagnosed mCSPC. There was a significant improvement in median overall survival with the addition of darolutamide (not reached) vs ADT plus docetaxel alone (48.9 months). The HR was 0.68 (95% CI: 0.57-0.80; P <.001). Similar findings were previously shown in the randomized phase III PEACE‑1 study, in which patients with de novo mCSPC received ADT and docetaxel with or without radiotherapy and/or abiraterone. In this study, the addition of abiraterone to ADT and docetaxel improved both overall survival and radiographic progression-free survival.
Both studies have shown that for patients who are candidates for docetaxel, adding one of these agents to ADT and docetaxel improves survival without additional safety concerns beyond what would be expected with the single agents themselves. However, neither of these studies provides clarity on how to appropriately select patients for docetaxel therapy. Hence, although such triplet therapeutic approaches may be appealing, I think that it is important to take caution when applying these results across all subgroups of patients with mCSPC.
In my opinion, nearly all patients who would have been considered to be eligible to receive docetaxel with ADT prior to the release of the results of the PEACE-1 trial of abiraterone and the ARASENS trial of darolutamide should be considered for triplet therapy based on Level 1 evidence for survival advantage with the addition of these agents in the phase III studies. However, darolutamide has not yet received FDA approval for mCSPC. The benefit of upfront docetaxel is greatest in patients with de novo presentation with high-volume disease, and the least benefit is in patients with low-volume metachronous disease. In this latter group of patients, however, I would favor “doublet therapy” with ADT and an AR pathway inhibitor.
Currently, the role of genetic testing in newly diagnosed mCSPC is controversial. There are ongoing biomarker-guided phase III trials in mCSPC. For example, the CAPItello-281 trial is for patients with PTEN deficiency; the TALAPRO-3 trial is for patients with DNA damage repair mutations; and the AMPLITUDE trial is enrolling patients with homologous recombination repair gene alterations. There are also other ways to target hormone signaling that are being studied in the castration-resistant settings, including the use of AR N-terminal domain blockers (eg, EPI-7386) and AR degraders (eg, bavdegalutamide). These are interesting compounds that are still early in development. If they exhibit clinical benefit and are found to have activity in advanced castration-resistant prostate cancer, they may become useful in the CSPC setting in the future.
Finally, in general, the adverse events of ADT are cumulative—the longer the exposure, the more likely that long-term complications will result. It is important to treat localized prostate cancer in an aggressive manner to ensure that the likelihood of cure is maximized and to decrease the probability that lifelong ADT will be needed in the future. For biochemically recurrent disease, I recommend treatment breaks, as intermittent ADT was demonstrated to be noninferior to continuous ADT in this setting. For some patients with mCSPC who undergo intensive treatment involving initial ADT in combination with an AR antagonist or abiraterone as well as localized treatment at the sites of disease, treatment breaks may also be considered. The phase II A-DREAM trial, which is investigating ADT interruption among patients with mCSPC who are responding exceptionally well to AR pathway inhibitors, will shed more light on the durability and quality-of-life benefits of treatment breaks in mCSPC. Overall, to maximize the quality of life for patients and to avoid the long‑term complications associated with continuous ADT, it is important to maximize the opportunity for curative intervention for localized disease and appropriately intensify treatment upfront for metastatic disease such that treatment breaks can be considered in the treatment strategy for selected patients.
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