Prostate cancer is the most common cancer among men in the UK, with more than 52 000 new cases diagnosed and nearly 12 000 deaths each year (Cancer Research UK, 2022). The development and progression of the disease is considered to be dynamic, with key milestones of disease states (Anantharaman and Small, 2017).
Recurrence of localised or locally advanced prostate cancer is initially managed by androgen deprivation therapy (ADT), by either surgical or pharmacological means post radical therapy (Anantharaman and Small, 2017; Drudge-Coates et al, 2018). Ultimately, most patients (~77%) develop resistance to ADT, despite having castration levels of testosterone, and the disease progresses to non-metastatic, castration-resistant prostate cancer (nmCRPC) (Liede et al, 2016) or ‘hormone-relapsed non-metastatic prostate cancer’ (National Institute for Health and Care Excellence (NICE), 2019a), evidenced by rising levels of prostate-specific antigen (PSA) (Anantharaman and Small, 2017; Drudge-Coates et al, 2018; El-Amm and Aragon-Ching, 2019).
In some cases, patients with rapidly progressing disease will develop metastases (Liede et al, 2016) and bypass the nmCRPC stage of the disease course; however, the majority of patients (86%) with metastatic castration-resistant prostate cancer (mCRPC) progress from nmCRPC (Scher et al, 2015), with one-third of patients with nmCRPC progressing to mCRPC within 2 years (Kirby et al, 2011).
The development of metastases is associated with higher mortality and morbidity than nmCRPC (Anantharaman and Small, 2017; Drudge-Coates et al, 2018; Fizazi et al, 2019a) and, therefore, a key treatment goal in nmCRPC is to delay progression to the metastatic state (Anantharaman and Small, 2017; El-Amm and Aragon-Ching, 2019; Fizazi et al, 2019a).
Historically, ADT was continued in patients with nmCRPC using first-generation androgen receptor inhibitors (ARis), luteinising hormone-releasing hormone (LHRH) agonists or switching between hormonal agents (Anantharaman and Small, 2017; El-Amm and Aragon-Ching, 2019). However, nmCRPC is highly heterogeneous and the response to these agents is variable (Anantharaman and Small, 2017; El-Amm and Aragon-Ching, 2019).
Before 2018, there was no clear consensus over the treatment of patients with nmCRPC (Esther et al, 2019), and many patients were frequently managed using a ‘watch and wait’ approach or were offered first-generation ARis such as bicalutamide (Suzuki et al, 2008; Lodde et al, 2010), flutamide (Suzuki et al, 2008) or oestrogen/ketoconazole (Suzuki et al, 2008; Lodde et al, 2010). However, none of these agents has demonstrated a survival benefit (Esther et al, 2019). The psychological burden of the watch and wait approach may be a disadvantage, with many patients reporting feelings of anxiety around rising PSA levels and depression, as well as concerns over the increased burden on family and friends (Burbridge et al, 2020).
Given the multidisciplinary approach to care, clinical nurse specialists play an integral role in prostate cancer management (Lewis et al, 2009; Fleure and Sara, 2020). This involves the monitoring of adverse events–defined as any undesirable experience associated with the use of a medical product in a patient (Food and Drug Administration Agency, 2016), educating and supporting patients on how to manage their disease and managing follow-up visits.
Recent changes in the nmCRPC treatment landscape
Second-generation ARis offer several advantages over first-generation agents: a higher affinity for the androgen receptor; no agonistic effects; and a multimodal mechanism of action (El-Amm and Aragon-Ching, 2019) (Figure 1).
Three such agents, apalutamide, enzalutamide and darolutamide (Fizazi et al, 2020; Sternberg et al, 2020; Smith et al, 2021), are licensed for use in the UK (Electronic Medicines Compendium (EMC), 2022a; 2022b; 2022c) and the EU (European Medicines Agency (EMA), 2019; 2021; 2022) for the treatment of nmCRPC in patients at high risk of metastatic disease, defined as patients with a PSA doubling time (PSADT) of ≤10 months) and PSA level ≥2 ng/ml (Oudard, 2019). Only darolutamide and apalutamide are recommended by NICE guidelines (NICE, 2020; 2021) for the treatment of adults with high-risk nmCRPC. In addition, darolutamide with ADT is recommended by the Scottish Medicines Consortium (SMC, 2020) for the treatment of patients with nmCRPC.
Apalutamide is a second-generation ARi (Smith et al, 2021) with stronger androgen inhibition activity than bicalutamide (El-Amm and Aragon-Ching, 2019). The pivotal phase 3 Study of Apalutamide in Men with Non-Metastatic Castration-Resistant Prostate Cancer (SPARTAN) showed that apalutamide, compared with placebo, improves overall survival (median overall survival: 73.9 versus 59.9 months; HR 0.78; 95% CI (0.64–0.96)) and delayed initiation of cytotoxic therapy in patients with nmCRPC (HR 0.63; 95% CI 0.49–0.81) (Smith et al, 2021).
Enzalutamide, which has a similar mechanism of action to apalutamide (El-Amm and Aragon-Ching, 2019), also showed a prolonged overall survival benefit compared with placebo in the phase 3 Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer (PROSPER) study (enzalutamide 67.0 months; 95% CI (64.0–not reached), placebo 56.3 months; 95% CI (54.4–63.0) respectively) (Sternberg et al, 2020).
The most recently approved second-generation ARi, darolutamide, is structurally distinct from apalutamide and enzalutamide (Moilanen et al, 2015; El-Amm and Aragon-Ching, 2019; Fizazi et al, 2020) and exhibits tighter binding to the androgen receptor than the other two agents, resulting in reduced activation of the genes required for prostate cancer cell growth and survival in an in vitro setting (Moilanen et al, 2015).
Darolutamide for nmCRPC
The approval of darolutamide in the UK for the treatment of adult men with nmCRPC who are at high risk of developing metastatic disease (EMC, 2022a), and its recommendation by NICE (2020) and the SMC (2020), were based on clinical evidence and estimated cost-effectiveness, and took into consideration the limited treatment options currently available for this patient population.
The key clinical data that led to the recommendation for darolutamide came from the Phase 3 Androgen Receptor Antagonizing Agent for Metastasis-free Survival (ARAMIS) trial (Fizazi et al, 2019a; 2020). In this double-blind, placebo-controlled trial, 1509 patients with nmCRPC were randomised to receive darolutamide 600 mg twice daily (n=955) or placebo (n=554), while continuing ADT (Fizazi et al, 2019a). The primary endpoint was metastasis-free survival, defined as the time from randomisation to confirmed evidence of distant metastasis on imaging or death from any cause, whichever occurred first (Fizazi et al, 2019a).
The median metastasis-free survival was 40.4 months in the darolutamide group compared with 18.4 months in the placebo group (Fizazi et al, 2019a). This finding was statistically significant, with an HR for metastasis or death of 0.41 (95% CI (0.34–0.50); P<0.001), and the benefit was observed across all subgroups (Fizazi et al, 2019a). The incidence of adverse events was similar in the two groups, and the majority were grade 1 or 2 in severity (Table 1) (Fizazi et al, 2019a). Notably, there were no significant differences in the incidences of seizures, dizziness or cognitive impairment, supporting the suggestion that darolutamide has low blood–brain barrier penetration (Pajouhesh and Lenz, 2005). An open-label extension of the ARAMIS study showed that the risk of death with darolutamide was 31% lower than with placebo after a median follow-up of 29.0 months (HR death 0.69; 95% CI (0.53–0.88); P=0.003) (Fizazi et al, 2020).
Table 1. Adverse events in darolutamide and placebo groups
| Darolutamide + androgen deprivation therapy (n=954) | Placebo + androgen deprivation therapy (n=554) | |
|---|---|---|
| Exposure, median (months) | 14.8 | 11.0 |
| Any adverse event, n (%) | 794 (83.2) | 426 (76.9) |
| Grade 3 or 4 | 236 (24.7) | 108 (19.5) |
| Grade 5 | 37 (3.9) | 18 (3.2) |
| Serious | 237 (24.8) | 111 (20.0) |
| Leading to permanent discontinuation of study drug | 85 (8.9) | 48 (8.7) |
Includes any fractures and dislocations, limb fractures and dislocations, skull fractures, facial bone fractures and dislocations, spinal fractures and dislocations, and thoracic cage fractures and dislocations
‡Includes dermatitis, erythema, rash, rash macular, rash maculopapular, rash papular and rash pustular
§Includes cerebral infarction, cerebral ischaemia, cerebrovascular accident, ischaemic stroke and transient ischaemic attack. Grade 5 events occurred in one patient receiving darolutamide and three patients receiving placebo
◊Includes coronary artery disorders not elsewhere classified, arteriosclerosis coronary artery, coronary artery disease, coronary artery occlusion, and coronary artery stenosis. Grade 5 events occurred in three patients receiving darolutamide and one patient receiving placebo
¶Includes heart failures not elsewhere classified, cardiac failure, acute cardiac failure, chronic cardiac failure, congestive cardiac failure and cardiogenic shock. Grade 5 events occurred in four patients receiving darolutamide and three patients receiving placebo
Detailed guidance on which patients may be suitable for treatment with darolutamide has been outlined by the national Cancer Drugs Fund Blueteq criteria for prescribing darolutamide; the Cancer Drugs Fund list can be found on the website of NHS England (2022). The key Blueteq criteria (Table 2) are based on the eligibility criteria from the ARAMIS trial (Fizazi et al, 2019a) and therefore reflect the patients most likely to benefit from darolutamide treatment.
Table 2. Key patient eligibility criteria for darolutamide
| 1 | Histologically or cytologically confirmed prostate cancer without neuroendocrine differentiation or small cell features (ClinicalTrials.gov, 2021) |
| 2 | No detectable clinical metastases on imaging (Fizazi et al, 2019a; ClinicalTrials.gov, 2021) |
| 3 | Prostate-specific antigen doubling time ≤10 months (Fizazi et al, 2019a; ClinicalTrials.gov, 2021) |
| 4 | Prostate-specific antigen ≥2 ng/ml (Fizazi et al, 2019a; ClinicalTrials.gov, 2021) |
| 5 | Eastern Cooperative Oncology Group performance status 0 or 1 (ClinicalTrials.gov, 2021) |
| 6 | Serum testosterone concentration <50 ng/ml (ClinicalTrials.gov, 2021) |
| 7 | Blood assessments (e.g. full blood count) (ClinicalTrials.gov, 2021) |
There are limitations on the use of darolutamide, enzalutamide and abiraterone in the overall prostate cancer treatment pathway (NICE, 2019a). Although both enzalutamide and abiraterone are recommended for mCRPC as well as nmCRPC, because of the similarity of all three agents, NICE guidelines do not recommend back-to-back use of second-generation ARis (NICE, 2019a). This means that, if a patient who was receiving darolutamide for nmCRPC develops metastases, there is an greater likelihood that they would receive chemotherapy treatment for metastatic disease (Payne, 2021).
Although many patients with nmCRPC are asymptomatic, they should be informed of the risks associated with delaying treatment (as in watchful waiting), including the earlier development of metastases (Esther et al, 2019). Given the survival benefits and maintenance of health-related quality of life associated with darolutamide compared with placebo plus ADT (Fizazi et al, 2019a; 2019b; 2020), in addition to the generally acceptable tolerability profile of darolutamide compared with placebo (Fizazi et al, 2019a; 2019b; 2020), the benefits of early treatment with darolutamide may outweigh the risks of delaying treatment.
To ensure an individualised approach to patient care is taken, decisions regarding treatment should include the patient in partnership with a health professional (NICE, 2019b).
Nursing role in nmCRPC
A multidisciplinary approach to care in prostate cancer, involving urologists, oncologists, GPs and CNSs, is essential for the timely identification of patients with nmCRPC who are suitable for darolutamide treatment (i.e. when PSADT is ≤10 months in addition to rising PSA), especially as most patients with nmCRPC are largely asymptomatic (Fizazi et al, 2019a).
CNSs play a pivotal role within the multidisciplinary team across the whole patient pathway (Figure 2) and NICE (2002) guidelines recommend that each patient has access to a named CNS who can provide support when and if required.
Diagnosis
The time of diagnosis of prostate cancer can be a sensitive one for both the patient and his family, and emotional support is therefore vital (Tarrant et al, 2008). Nurse specialists are usually present at diagnosis and, in some centres, they may be the health professional responsible for communicating the diagnosis to the patient (Fleure and Sara, 2020).
Once a diagnosis has been made, CNSs are also responsible for educating patients about their disease and the likelihood of progression and for providing advice about individualised treatment options for nmCRPC and beyond, such as information on second-generation ARis, ADT and additional agents such as bone health agents in patients newly diagnosed with nmCRPC.
Holistic support continues far beyond diagnosis. CNSs are heavily involved in patient care, and act as advocates throughout the prostate cancer treatment pathway (Fleure and Sara, 2020). Support includes empathising with the patient throughout their treatment journey and helping address any anxiety regarding rising PSA levels, as well as providing healthy lifestyle advice and guidance on how to manage potential treatment-related problems (including adverse events and erectile dysfunction) (Paterson et al, 2019; Fleure and Sara, 2020; EMC, 2022a).
Follow-up and monitoring: role of the uro-oncology CNS in managing adverse events
CNSs can take responsibility for adverse event monitoring and management, sometimes in collaboration with an oncology pharmacist. Early management of adverse events, whether treatment related or not, is likely to improve drug adherence and reduce chances of therapy discontinuation.
The most common adverse event related to darolutamide is fatigue, which has been reported in approximately 16% of patients (EMC, 2022a). Other adverse events of interest include fractures, ischaemic heart disease and heart failure, and alterations in neutrophil, bilirubin and aspartate aminotransferase levels.
By monitoring the occurrence of adverse events, CNSs are able to advise if doses may need to be modified. They can also advise the patient that the risk of neurological effects, such as seizures, with darolutamide is relatively low because it does not cause localised reductions in cerebral blood flow (Williams et al, 2020).
Follow-up and monitoring: the role of uro-oncology CNSs in assessing for drug–drug interactions
An important aspect of the CNS role when a patient is followed up in clinic is to understand his current medication, including concomitant prescribed and non-prescribed drugs, to reduce the potential for drug-drug interactions.
The pharmacokinetic profile of darolutamide means that it is potentially susceptible to drug interactions with enzyme inducers; furthermore, it should be used with caution when co-administered with drugs that prolong the QT interval (EMC, 2022a).
A detailed medication history will enable the identification of any potential drug-drug interactions, which can be managed according to the summary of product characteristics.
Nurse-led clinics in nmCRPC
Pressure is increasing on NHS resources owing to the rising prevalence of prostate cancer across the UK (Prostate Cancer UK, 2019) and the associated need to support patients throughout the entire treatment pathway. Increasing the provision of nurse-led services in prostate cancer has been highlighted as an urgent need by the Department of Health (2007).
CNSs are in a unique position to deliver care to these patients and help reduce appointment cancellations and unnecessary hospital admissions, alleviating doctors' workloads and increasing the level of care that is delivered in the community (Read, 2015). The authors also acknowledge that, given the overlap in shared knowledge (Cooper et al, 2019), there could be a place for advanced nurse practitioners in supporting prostate cancer care.
It has been demonstrated that nurse-led follow-up clinics for men after treatment for localised prostate cancer can be delivered at high volume with high levels of patient satisfaction (Leahy et al, 2013; Casey et al, 2017; Martin et al, 2018). These follow-up clinics can be delivered face to face, by phone or remotely (Leahy et al, 2013; Casey et al, 2017) to enable the identification of patients at high risk of disease progression through regular PSA surveillance and permit the review and discussion of treatment options with the patient in accordance with NICE (2019b) guidelines.
Many non-medical prescribing nurses can conduct reviews of treatment dosages, assess the potential for dose reduction/escalation and prescribe a new treatment dose after the first dose prescribed by an oncology consultant.
Once established on treatment for approximately 3 months, many patients with prostate cancer move to nurse-led telephone consultations, in particular PSA telephone follow-ups, which are increasingly becoming an essential part of patient care within the uro-oncology outpatient clinic.
In addition, CNSs are responsible for the proactive identification and assessment of disease relapse or progression and referral of patients back into secondary care if required (Fleure and Sara, 2020): these factors are important for faster diagnosis and treatment (Corner, 2003) and for improving productivity and efficiency within the healthcare service (Baxter, 2011; Kerr et al. 2021).
Case studies
There is evidence to suggest that support from a CNS improves a patient's outlook and experience of care (Tarrant et al, 2008). Here, the authors present two evidence-based case studies which highlight the treatment and management of two patients diagnosed with nmCRPC and how they were supported by a uro-oncology CNS. Adverse events experienced by patients were reported following the necessary procedures.
Patient case study 1
A 60-year-old man had a PSA level of 61 ng/ml. A prostatic biopsy revealed a Gleason score 7 (3+4) adenocarcinoma of the prostate. His past medical history included type 2 diabetes and hypertension.
Staging and diagnosis
Based on results from prostate biopsy evaluation and imaging investigations, non-metastatic prostate cancer was diagnosed. The tumour had extended bilaterally through the prostatic capsule (T3b); no metastases were found in the bone (M0) and the cancer had not spread to the nearby lymph nodes (N0).
Treatment history
The patient was treated with LHRH agonists for 3 years and received radical radiotherapy.
Concomitant medications
The patient was also receiving amlodipine, aspirin, atorvastatin, bisoprolol, candesartan, leuprorelin and omeprazole.
Management and follow-up
The patient was followed up in a nurse-led clinic for the duration of hormone therapy. His PSA level began to rise after nearly 3 years of LHRH treatment, so hormone manipulation was continued.
Three years later, the CNS identified that the patient was experiencing perineal pain and his PSA level was 2 ng/ml, so he was referred to the oncology department for a positron emission tomography scan. No recurrence was observed.
Regular PSA surveillance was continued by an oncologist, and the patient remained fit and healthy. The patient contacted a uro-oncology CNS for emotional support during the lead-up to his routine PSA assessment because of anxiety regarding his PSA levels.
Two years later, the patient's PSA level had risen to 22 ng/ml, with a PSADT of 6 months and a castrate testosterone level of 0.4 nmol/l. Restaging scans were negative for metastases. The patient remained asymptomatic and otherwise well. He was referred to the oncology department for consideration of treatment with darolutamide; he met the eligibility criteria and began treatment. Before the patient was started on darolutamide, the CNS advised him to stop treatment with atorvastatin and switch to simvastatin or pravastatin because of the potential the drug-drug interaction.
The CNS gave the patient an information booklet with advice about emotional support, potential adverse events and how to live a healthy lifestyle; the CNS also discussed the possible adverse events in detail with the patient. Owing to the patient's history of hypertension, the CNS advised him to monitor his blood pressure (BP) at home twice weekly and to contact a member of the nursing team if he had any concerns..
Monitoring while on treatment with darolutamide
At month 1, the patient's PSA level had reduced to 9.6 ng/ml. The patient said his memory was not as sharp as before. He was encouraged to exercise and continue monitoring his BP; BP was 135/74 mmHg.
At month 2, his PSA level was 4.7 ng/mL. The patient was exercising frequently, attending the gym four times per week. Issues with his memory had disappeared and he felt less tired. BP was 135/74 mmHg.
At month 4, his PSA level had decreased to 3.23 ng/ml. The patient continued to exercise frequently and his BP was 135/80 mmHg. He experienced fewer hot flushes compared with previous months and his quality of life had improved. His anxiety around rising PSA levels had also reduced and there were fewer reported calls to the uro-oncology CNS team for support around the time of PSA testing.
Patient case study 2
An 80-year-old man presented with a PSA level of 33 ng/ml. Prostatic biopsy revealed a Gleason score 9 (5+4) adenocarcinoma of the prostate. His past medical history included hypertension and benign prostatic hyperplasia.
The patient was being monitored in a nurse-led prostate clinic and was identified as having a rising PSA level. He was referred back to his oncology consultant to arrange restaging scans.
Staging and diagnosis
Based on results from prostate biopsy evaluation and imaging investigations, a diagnosis of non-metastatic prostate cancer was made in December 2008. The tumour had extended bilaterally inside the prostate gland (T2c); no metastasis was found in the bone (M0) and the cancer had not spread to the nearby lymph nodes (N0).
Treatment history
Upon initial discussions between the patient, CNS and oncologist, the patient began immediate hormone therapy and received radical radiotherapy to the prostate, which was completed in June 2009. Hormone therapy was ceased in June 2011. In January 2017, biochemical relapse was diagnosed, and the patient started treatment with hormonal manipulation in February 2017. Progressive disease was diagnosed in November 2018—the PSA level was 5 ng/ml—and he started maximum androgen blockade treatment.
In early 2020, through telephone clinic follow-up, the CNS identified the patient was demonstrating a rising PSA level. His PSA level had increased from 10.4 ng/ml in February 2020 to 16.8 ng/ml (May 2020) to 26.7 ng/ml in August 2020).
He was referred to oncology for restaging scans. The bone scan was negative for metastases and a computed tomography scan demonstrated pelvic lymph nodes were ≤2 cm. The castrate testosterone level was <0.4 nmol/l. A diagnosis of nmCRPC was confirmed and the treatment options were discussed with the patient. Darolutamide treatment was started in September 2020.
Concomitant medications
The patient was also receiving goserelin, ramipril and tamsulosin.
Management and follow-up
Once on treatment with darolutamide, the patient returned to the nurse-led prostate clinic for ongoing monitoring. The uro-oncology CNS monitored the patient's PSA level and adverse events and ensured he was on the most appropriate treatment.
Support by an assigned CNS ensured the patient received continual care and maintained the rapport fostered over many years.
Darolutamide treatment reduced the patient's PSA level, with the lowest level recorded as 1.47 ng/ml. The patient has been on treatment for 17 months and his PSA level is currently low and stable. Treatment with darolutamide has been well tolerated, with mild fatigue but no other adverse events or toxicities reported to date.
Conclusion
Approval of the second-generation anti-androgens apalutamide, enzalutamide and darolutamide has changed the treatment landscape for patients with nmCRPC as they have several advantages over first-generation agents.
Darolutamide is recommended by NICE (2020) and the SMC (2020) in the UK for the treatment of adult patients with nmCRPC who are at high risk of developing metastatic disease, as it has been shown to significantly prolong metastasis-free survival.
CNSs are valuable members of the multidisciplinary team and play a pivotal role throughout the prostate cancer pathway.
The authors make the following key recommendations for the pivotal role of CNSs in prostate cancer management, which includes that they:
- Aid in the identification of patients at high risk of disease progression through regular PSA surveillance and permit the review and discussion of available treatment options with the patient (NICE, 2019b)
- Provide emotional support to the patient and his family throughout the entire patient pathway (Tarrant et al, 2008)
- Conduct a holistic needs assessment to ensure the patient's individual needs are identified and the appropriate treatment initiated upon diagnosis (Fleure and Sara, 2020)
- Provide healthy lifestyle advice and guidance on how to manage potential treatment-related problems (including adverse events and erectile dysfunction) (Paterson et al, 2019; Fleure and Sara, 2020;).
KEY POINTS
- The approval of second-generation androgen receptor inhibitors has changed the treatment landscape for patients with non-metastatic, castration-resistant prostate cancer (nmCRPC)
- Darolutamide is recommended in the UK for the treatment of men with nmCRPC who are at high risk of developing metastases, based on evidence that it significantly prolongs metastasis-free survival versus placebo
- It is important to identify which patients are eligible to receive darolutamide according to the Blueteq approval criteria, and nurses can play a key role in this assessment
- Clinical nurse specialists are important members of the multidisciplinary team, with a special focus in the management and care of patients with prostate cancer, patient education and monitoring for adverse reactions
- The provision of nurse-led services in prostate cancer is vital for delivering care to support patients given the ever-increasing demands on the NHS
CPD reflective questions
- In what ways can clinical nurse specialists (CNSs) support patients with prostate cancer throughout the patient pathway?
- How can CNSs improve the quality and experience of care for patients?
- How can nurse-led clinics improve the identification of patients with nmCRPC?