Safety differences across androgen receptor inhibitors in nonmetastatic castration-resistant prostate cancer

Background

Nonmetastatic castration-resistant prostate cancer

Prostate cancer is the second most common cancer among men, with more than 1.4 million new cases worldwide in 2020 and an estimated 268,490 new cases in the USA for 2022 [1,2]. The majority of prostate cancer cases in the USA (~75%) are nonmetastatic at diagnosis [3,4]. However, up to one-half of localized cases progress to biochemical recurrence after primary treatment (e.g., radiation therapy or radical prostatectomy), typically within 5 years, at which point androgen deprivation therapy (ADT) via surgical or chemical castration is the standard-of-care [5–7]. A significant subset of men treated with ADT will experience elevated prostate-specific antigen (PSA) concentrations again and eventually develop castration-resistant prostate cancer (CRPC), characterized as a castrate serum testosterone level of <50 ng/dl despite ADT or orchiectomy [8]. Patients with nonmetastatic CRPC (nmCRPC) do not have radiologically detectable metastases by conventional imaging but are at risk of progression to metastatic disease and thus worsening clinical outcomes [9,10].

Treatment landscape for nmCRPC: approval of second-generation androgen receptor inhibitors

The treatment of nmCRPC has long been an area of unmet need, and until recently, treatment options were limited and there was no consistent standard-of-care [10,11]. This changed in 2018–2019 when the US FDA approved three second-generation androgen receptor inhibitors (ARIs) – apalutamide, enzalutamide and darolutamide – for nmCRPC [12,13], which offered improved efficacy over ADT and greatly expanded therapeutic options. Approvals of these three second-generation ARIs were made on the basis of results of the phase III clinical trials SPARTAN (apalutamide), PROSPER (enzalutamide) and ARAMIS (darolutamide). These trials each demonstrated that treatment with the second-generation ARIs in combination with ADT conferred significant benefits for improving metastasis-free survival (MFS) versus placebo plus ADT in patients with nmCRPC [14–16]. Subsequent analyses of these trials have also demonstrated all three second-generation ARIs to be associated with significantly improved overall survival (OS) compared with placebo plus ADT [17–19]. Accordingly, in 2020, the treatment guidelines for advanced prostate cancer from the American Urological Association were updated to strongly recommend apalutamide, enzalutamide or darolutamide in combination with ADT with evidence level grade A (high certainty) for nmCRPC [20].

Treatment selection in nmCRPC: the importance of safety considerations

The availability of apalutamide, enzalutamide and darolutamide has raised the question of choice of treatment for patients. When considering pharmacological options, shared decision-making between patients and providers should evaluate the risk–benefit profile of the treatment – its ability to delay disease progression (time to metastases) against potential drug safety considerations – which can have meaningful and far-reaching impacts on patient quality of life (QoL). These considerations include the occurrence of adverse events (AEs) along with potential drug–drug interactions (DDIs).

In this perspective, we discuss the efficacy and safety of apalutamide, enzalutamide and darolutamide, and suggest that for patients with nmCRPC, who are typically asymptomatic, safety considerations (including AEs) for these treatments are especially critical. We examine the importance of these considerations in the context of a recent preference study among patients with nmCRPC and their caregivers, a survey study among patients with nmCRPC, and within the context of clinical characteristics of patients with nmCRPC [21,22]. We further posit that consideration of treatments’ safety profiles should include not only the initial direct impacts from AE and DDI events, but the full cascade of additional and potentially avoidable complications of care that may ensue. As we later discuss, these after-effects may arise in part because of discontinuation of therapy due to AEs [23] as well as the need for additional pharmacotherapy or other modalities, which can have implications for patient and caregiver wellbeing and daily activities (e.g., lost work productivity due to absenteeism [absence from work] and presenteeism [reduced productivity while at work]), all of which in turn may potentially contribute to substantial indirect medical costs [23,24].

Efficacy & safety profiles of apalutamide, enzalutamide & darolutamide

Evidence from the pivotal clinical trials: SPARTAN, PROSPER & ARAMIS

Prior pivotal clinical trials for apalutamide, enzalutamide and darolutamide showed strong clinical benefit for each of the treatments compared with placebo in extending MFS and OS [14–16]. Additionally, the SPARTAN, PROSPER and ARAMIS trials demonstrated favorable results for all three second-generation ARIs in maintaining QoL. For example, the SPARTAN trial revealed that QoL deterioration was more apparent in the placebo group than in the apalutamide group [14]. Additionally, patients in PROSPER who were treated with enzalutamide exhibited more favorable results than those in the placebo group for most domains of the Functional Assessment of Cancer Therapy – Prostate (FACT-P) questionnaire, a health-related QoL tool for prostate cancer; the exception to this trend was physical wellbeing [15]. In the ARAMIS trial, patients treated with darolutamide versus placebo had significantly delayed time to urinary symptoms, as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire prostate cancer module (EORTC-QLQ-PR25) [16,25]. Darolutamide and enzalutamide were also associated with significantly delayed time to pain progression (as measured by the Brief Pain Inventory Short Form [BPI-SF] questionnaire) [15,16]. Moreover, this delay in time-to-pain progression was maintained beyond end of study treatment for darolutamide [15,16].

The pivotal trials for apalutamide, enzalutamide and darolutamide also documented safety outcomes. The trials confirmed increased incidence of certain AEs with apalutamide, enzalutamide and darolutamide versus placebo plus ADT. Table 1 summarizes the commonly occurring AEs for each treatment (≥10% with ≥2% over placebo) related to nmCRPC, as published in their prescribing information [26–28].

Comparative efficacy of the second-generation ARIs

Although no head-to-head direct comparator trials exist comparing apalutamide, enzalutamide and darolutamide in nmCRPC, evidence from several indirect treatment comparisons has provided additional insights regarding the comparative efficacy across the second-generation ARIs. For instance, studies by Mulati et al., Roumiguié et al. and Halabi et al., which used network meta-analyses (NMAs) and matching-adjusted indirect comparisons (MAICs), found no significant differences among the three treatments in terms of MFS [29–31]. For OS, statistically significant differences were not detected, but nominal differences in the hazard ratios pointed toward darolutamide having the highest probability of achieving longer OS [31].

Safety profile differences across the second-generation ARIs

In contrast with the efficacy results, the safety profiles of apalutamide, enzalutamide and darolutamide have exhibited statistically significant differences and, in many cases, clinically meaningful differences favoring darolutamide in indirect treatment comparison analyses [30]. Although the second-generation ARIs share some AEs (e.g., hypertension), apalutamide and enzalutamide are associated with a higher risk of CNS events compared with darolutamide in these analyses. These differences in AE profiles may be attributed, in part, to differences in the drugs’ chemical structure and molecular size. Although all three second-generation ARIs work in a similar fashion mechanistically, darolutamide exhibits a much lower propensity for crossing the blood–brain barrier, resulting in a lower risk of CNS-related events compared with apalutamide and enzalutamide [32,33]. For instance, an anchored MAIC by Halabi et al. that controlled for cross-trial differences in patient baseline characteristics, exclusion criteria and study duration found that darolutamide was associated with significantly lower absolute risks for falls and fractures compared with both apalutamide and enzalutamide, as well as significantly lower absolute risk of mental impairment disorder compared with enzalutamide (risk of mental impairment disorder was numerically lower than apalutamide) [30]. Similarly, a risk difference analysis in a NMA by DiNunno et al. comparing the three treatments found a significantly higher risk of fractures for apalutamide and no higher risk for darolutamide compared with placebo (relative risk of fracture was not reported for enzalutamide) [34]. The incidence of falls and fractures with apalutamide and with enzalutamide are particularly notable; patients are recommended to be evaluated for fall/fracture risk before initiating those therapies per their US prescribing information [26,27]. While the evidence from the aforementioned indirect comparisons is not a substitute for head-to-head trials that directly compare the treatments, these studies provide the best comparative evidence in the absence of randomized trials and help to mitigate differences that have been noted across the trials that may serve as confounders [35].

In addition to the safety considerations noted above, potential DDIs differ across the three second-generation ARIs (Table 2), with potential interactions being most prevalent for apalutamide [26–28]. More specifically, for apalutamide, potential DDIs include impacts to the activity of medications that are sensitive substrates of CYP3A4, CYP2C19, CYP2C9, UGT, P-gp, BCRP or OATP1B1 [26]. Additionally, coadministration with strong CYP2C8 or CYP3A4 inhibitors can impact apalutamide, increasing the steady-state exposure of its active moieties [26]. For enzalutamide, potential DDIs include CYP2C8 inhibitors and sensitive substrates of CYP3A4, CYP2C9 and CYP2C19 [27]. For darolutamide, potential DDIs consist of interactions with P-gp and CYP3A4 inducers/inhibitors and substrates of BCRP, OATP1B1 and OATP1B3 [28].

A closer look at safety events & CNS-related events in particular

Considerations for the nmCRPC population

Careful appraisal of treatments’ AE profiles and potential for DDIs is critical in the nmCRPC population and their individualized treatment selection. Although patients with nmCRPC are generally asymptomatic from a tumor burden perspective, they frequently are older with a median age over 75 years [36,37] and a greater comorbidity burden, often requiring concomitant medications [38]. These comorbidities frequently include cardiovascular conditions such as hyperlipidemia, hypertension, arrhythmias and congestive heart failure. For instance, Appukkuttan et al. found that among patients with nmCRPC, 96% had hypertension and 88% had a myocardial infarction, as reported by their physicians [38]. As such, patients are often on statins, antiplatelet agents, angiotensin-converting enzyme inhibitors, β-blockers and calcium channel blockers [39,40]. In addition to these age-related comorbidities, patients may be experiencing symptoms from ADT treatment such as loss of bone density and muscle mass, placing them at heightened risk for falls, fracture and frailty, which may not reverse even after ADT cessation [41–43]. These factors increase the potential for severe harm from treatment-emergent AEs such as CNS-related events and DDIs [5,44].

Importance of CNS-related events

CNS-related events can dramatically impact patients’ clinical burden, healthcare resource utilization (HCRU) and cost of care [45,46]. In fact, patients, caregivers and physicians are especially concerned about cognitive impairment, falls and fractures [47]. A recent stakeholder preference study showed that patients with nmCRPC and their caregivers prioritized avoiding these three events during treatment over extending OS [21]. From a clinical perspective, CNS-related AEs are particularly noteworthy due to their potential to lead to increased morbidity, reduced QoL and decreased efficacy of cancer treatment (e.g., due to dose interruptions or reductions, or diminished treatment adherence) among patients with advanced prostate cancer [48]. Moreover, CNS-related events often do not occur as isolated events and may trigger a cascade of healthcare interventions. For example, dizziness may lead to falls, which in turn may lead to fractures – events that can be particularly concerning in an older patient population, precipitating major disability and even loss of independence. Below, we provide more context on each of these aspects, including examples of cascades of care and the associated healthcare journeys for patients experiencing falls and fractures (Figure 1) and cognitive impairment (Figure 2). Considerations of treatments’ safety profiles (including AEs and DDIs) should extend beyond direct drug costs and immediate HCRU and include the broader implications on the cascade of care and the ensuing direct and indirect HCRU and costs.

HCRU & cost implications: immediate & downstream effects

AEs and their subsequent management can contribute to high economic burden in oncology patients [45], including those with nonmetastatic prostate cancer [23,49]. A real-world study by Hussain et al. that focused on patients with nmCRPC found that treatment with apalutamide and enzalutamide required substantial use of AE management strategies [49]. These included initiating treatment for the AE (38% of patients), discontinuing ARI treatment (10.4%), ARI dose reduction (7.6%) and hospitalization (4.8%) [49]. In addition, using data from the ARIs’ pivotal trials and unit cost data, Shore et al. found that the main driver of the cost differences of grade ≥3 AEs between darolutamide and apalutamide was fracture, while the main driver between darolutamide and enzalutamide was fatigue, both of which may be triggered by, or related to, CNS events [50].

Recent real-world studies have also documented the high HCRU and costs associated with AEs in patients with nmCRPC who received enzalutamide or apalutamide, and with CNS-related AEs in particular. In a 2021 claims database analysis by Appukkuttan et al. [46], patients treated with enzalutamide or apalutamide who experienced CNS-related AEs had higher utilization of healthcare resources than patients without them, as noted by increased rates of inpatient (38 vs 4%, respectively) and emergency room (41 vs 14%) events, as well as a longer median length of inpatient stay (5 vs 2 days). The study further noted the significantly higher healthcare costs incurred by patients experiencing AEs with enzalutamide or apalutamide, with cost differences of US$30,765 (2021 USD) per-patient-per-year (PPPY; p = 0.0018) for those experiencing any AEs versus none [46]. For patients experiencing CNS-related AEs versus none, the cost difference was as much as $40,689 PPPY (p = 0.0017) [46].

The varying potential for DDIs across the three second-generation ARIs can also lead to differences in HCRU and associated cost implications. In another claims database study by Appukkuttan et al. [44], patients with nmCRPC treated with apalutamide and enzalutamide had a high prevalence of potential DDIs, driven by high rates of polypharmacy (76–80% of patients having five or more medications) and comorbidities that are common among patients with nmCRPC. Enzalutamide and apalutamide both have the potential for DDIs with medications that are often prescribed for chronic, comorbid conditions commonly encountered in the aging population with prostate cancer (e.g., anxiety, depression), where the loss of efficacy due to DDIs could leave patients at greater risk of cognitive impairment associated with these comorbidities [51]. This, in turn, may require stricter monitoring, with accordingly higher HCRU and costs. Thus patients with nmCRPC may benefit from drugs with lower interaction potential, which darolutamide may offer [51,52].

Furthermore, treatment-related AEs may increase downstream direct medical costs; these include costs incurred through increased physician monitoring and treatment of the AE instead of the patient’s primary condition. They may also include costs from the accompanying cascade of care that may extend to other healthcare providers and additional workups, tests, or treatment. Experiencing AEs may also impact indirect medical costs, such as loss of work productivity and disruption to the daily activities and overall wellbeing of the patients' caregivers.

Disruptions to treatment compliance & issues with prescribing cascades

A crucial consideration for treatment selection is the detrimental impact that AEs can potentially have on treatment plans and clinical outcomes, such as dose delays or reductions, lower adherence and discontinuation [53]. For example, patients with nmCRPC who experience AEs during treatment have been shown to be more likely to discontinue therapy, particularly after a CNS-related AE, which may increase the risk of disease progression [23].

Physicians should also be aware of the risk of a prescribing cascade, a scenario ‘when a drug is prescribed, an adverse drug event occurs that is misinterpreted as a new medical condition, and a subsequent drug is prescribed to treat this drug-induced AE' [54–56]. Prescribing cascades can lead to downstream adverse DDIs or other physical, emotional and QoL harms experienced by the patient. These can also strain the patient–physician relationship and lessen a patient’s trust in the advanced prostate cancer decision-making paradigm [57–60].

Conclusion

Enzalutamide, apalutamide and darolutamide provide similar MFS, with indirect treatment comparison evidence regarding OS suggesting that darolutamide may provide optimal OS in nmCRPC [31]. There is extensive literature on their safety profiles differing substantially [30,31]. Given the considerable economic burden of AEs and potential DDIs, including their downstream effects on treatment plans, clinical outcomes and patient QoL, prescribing decisions for nmCRPC should weigh the efficacy benefits against the safety profile of available treatments. Future research should focus on understanding the real-world effectiveness of the second-generation ARIs by investigating whether the differences in safety profiles may translate into differences in real-world adherence (discontinuation), which, in turn, may lead to differences in real-world effectiveness.

Future perspective

nmCRPC has historically been a heterogeneous disease stage, with some patients progressing rapidly while others remain in an indolent disease state. Anticipating future directions, advances in imaging and biomarker technology may alter our understanding of the nmCRPC disease stage and thus further inform treatment selection. For instance, development of next-generation imaging technologies such as anti-1-amino-3–18F-fluorocyclobutane-1-carboxylic acid scans and prostate-specific membrane antigen-based PET scans have allowed detection of much smaller metastases which conventional imaging (such as bone scans, CT scans or MRI) may have not detected, thereby reclassifying nonmetastatic versus metastatic CRPC [61–64]. The reclassification of patients to metastatic CRPC staging who would have previously been identified with nmCRPC under conventional imaging may improve the prognosis of both metastatic and nonmetastatic CRPC groups by virtue of a ‘Will Rogers phenomenon’-type effect – that is, shifting patients from one group to another, thereby raising the average of both groups [65]. However, it is unclear how the actual prognosis of these reclassified patients may change, as treatment strategies for patients with non-metastatic versus metastatic CRPC may differ.

In addition to advances in imaging, identification of genetic biomarkers with prognostic or predictive power may allow more granular classification of patients to inform treatment selection. In the longer term, future studies are needed to better understand the implications of these developments on treatment selection, including potential impacts on efficacy and safety across the second-generation ARIs.

Pending broad diffusion of these new imaging technologies and knowledge from additional studies, the safety considerations previously discussed for the second-generation ARIs remain important factors in patients’ and providers’ shared decision-making in treatment selection. Physicians should keep in mind not only the initial direct impacts from potential treatment-emergent AEs and DDI events, but also the full cascade of potentially avoidable healthcare complications. Additional research should focus on understanding real-world treatment patterns such as adherence and discontinuation related to ARIs’ safety events.