Enzalutamide, a novel hormonal therapy (NHT), in combination with androgen deprivation therapy (ADT), has emerged as one of the novel treatment options for metastatic hormone-sensitive prostate cancer (mHSPC).¹ The latest guidelines from the American Society of Clinical Oncology (ASCO) recommend the combination of enzalutamide with ADT as a standard of care (SoC) for mHSPC.² In an interview with Omnihealth Practice, Dr. Lam, Ho-Ching Martin shared his experience managing a case of mHSPC using the enzalutamide and ADT combination. He discussed the factors influencing the selection of enzalutamide, which included clinical considerations on the patient's comorbidities, as well as patient preferences such as the desire to avoid chemotherapy. Lastly, Dr. Lam highlighted data from the ARCHES trial, demonstrating the robust efficacy of the enzalutamide and ADT combination, supporting the use of this combination in his clinical practice.

Background

ADT and NHT doublet: The backbone of mHSPC management Prostate cancer (PC) has the 2^nd highest incidence and is the 3^rd leading cause of cancer death among men globally.¹ Although most (89%) of the newly diagnosed cases are locoregional, approximately 6% of patients are diagnosed at the metastatic stage, inferring a 5-year relative survival of barely over 30%.¹ ADT has been the mainstay of PC management since the 1940s.¹ Since then, the addition of NHT to ADT in patients with mHSPC has been extensively studied, demonstrating increased overall survival (OS) and progression-free survival (PFS), replacing ADT only as the SoC.¹

The latest ASCO guidelines on the initial management of advanced, recurrent, or metastatic HSPC recommends the doublet treatment of enzalutamide and ADT as one of the five SoC for patients with non-castrate metastatic PC, which also include those with de novo metastatic disease and received prior treatment such as radical prostatectomy or radiotherapy for localized disease.² Dr. Lam added that regardless of the patient’s risk category and disease volume, the SoC for mHSPC should include ADT + NHT such as enzalutamide. The decision to add chemotherapy or radiotherapy would be made based on the patient’s disease volume.

Selecting the right treatment modality based on patients’ profile
When managing patients with mHSPC, the selection of systemic treatment should be individualized, with the patient’s preference, comorbidities and contraindications taken into consideration.³ Dr. Lam emphasized that there is a myriad of factors to be considered when selecting a suitable NHT, highlighting the importance of tailoring the therapy to the patient’s characteristics.

One of the guiding factors in treatment selection for mHSPC is disease volume as patients with high- or low-volume disease have distinct prognoses.4 For patients with high-volume disease (defined as the presence of visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis), doublet therapy (NHT + ADT) and triple therapy with (NHT + ADT + chemotherapy) are both recommended in the ASCO guidelines.² In patients with low-volume disease, patients would most likely benefit from the addition of NHTs like enzalutamide and apalutamide to conventional ADT.⁴

Another deciding factor for the treatment selection of mHSPC is quality of life (QoL), which is viewed as an essential objective in patients receiving anticancer therapies since an impaired baseline QoL has been associated with poor survival outcomes.⁵ Docetaxel, being one of the commonly utilized cytotoxic agents for solid malignancies including PC, is associated with side effects such as alopecia, nausea and diarrhea.⁵ Dr. Lam noted that most patients are concerned about the AEs of chemotherapy, with alopecia in particular being a common concern among his patients, citing it as the major reason that patients refuse triplet therapy in combination with chemotherapy.

Factoring in the DDI and AE profile of different NHTs
Since most mHSPC patients are elderly individuals who require multiple treatments for chronic complications such as hypertension and diabetes, it is important to consider the safety and drug-drug interaction (DDI) profile of each NHT agent.⁶ Dr. Lam pointed out that abiraterone, an androgen synthesis inhibitor, is associated with lower limb edema and not suitable for patients with uncontrolled diabetes or heart diseases. Also, as an inhibitor of the CYP17 enzyme, abiraterone can disrupt lipid and glucose metabolism, leading to the development of metabolism-related AEs.6 Additionally, it is associated with an increased rate of hepatic disorders.⁶

Similarly, Dr. Lam highlighted the concerns of dermatological toxicities in apalutamide, cautioning that it should be avoided in patients with baseline skin conditions. Other common AEs of apalutamide include fatigue, fracture and fall, which can be attributed to reduced androgen levels.⁶ In his clinical practice, He opted for the combination of enzalutamide and ADT for managing mHSPC patients. He noted that elderly patients may face increased fall risk due to treatment-induced fatigue, which can be mitigated by administering enzalutamide at bedtime or initiating it at a lower dose. To illustrate how he incorporates the various considerations in choosing an appropriate treatment for patients in his clinical practice, Dr. Lam shared the following case.

Case sharing

A 60-year-old man who presented with bone pain was hospitalized in May 2022 (table 1). He had no family history of PC but was a chronic smoker with comorbid hypertension and hyperlipidemia. At presentation, a computed tomography (CT) scan showed multiple sclerotic bone metastasis, and his prostate-specific antigen (PSA) was also in the range of 400ng/mL-500ng/mL, indicating a high-volume disease despite no visceral metastasis. Prostate biopsy was subsequently performed, which confirmed the diagnosis of PC.

Despite his comorbidities, the patient was still relatively young and fit for triplet therapy with ADT, NHT and chemotherapy. However, the patient was highly concerned about the side effects of chemotherapy and wished to keep his diagnosis hidden from his family and friends. After an in-depth discussion with the patient, it was determined that the goal of therapy was not just to prolong survival, but also to maintain QoL and minimize the toxicities of the treatment. After assessing the risks and benefits of triplet therapy, the patient objected to the use of docetaxel due to the potential for hair loss, thus a doublet therapy of enzalutamide and ADT was initiated instead.

After 1 month of treatment, the patient’s PSA levels had already returned to <100ng/mL, and at 3 months, the PSA had dropped to single digits. After 6 weeks of treatment, the patient no longer required any pain medications for bone pain. The patient has been on treatment for over a year and the PSA was maintained at <1ng/mL. Initially, the patient was followed up every 2 weeks for the first 2 months, and is now followed up every 6-8 weeks. No further CT scans had been conducted as the recent PSA values showed no signs of rebound.

Overall, the therapy was well-tolerated at the full dose of enzalutamide (160mg daily). There were minor fluctuations in blood pressure which was promptly addressed with minor dose adjustments in antihypertensive medications. The patient reported mild fatigue but retained his productivity for his full-time office job. Overall, he was very satisfied with the treatment outcome, maintaining a low PSA while avoiding the burden of chemotherapy and its associated impact on QoL.

Discussion

rPFS regardless of subgroup with enzalutamide in ARCHES The balanced outcomes of the enzalutamide and ADT doublet therapy seen in the case sharing were reflected in the ARCHES trial, a multinational, double-blind, randomized phase 3 trial where 1,150 men with mHSPC were randomized to receive enzalutamide 160mg/day (n=574) or a matching placebo (n=576) on top of ADT.7 The findings of this study indicated a significantly reduced risk of radiographic disease progression or death associated with the addition of enzalutamide (HR=0.63; 95% CI: 0.52-0.76) (figure 1).⁸ The median radiographic progression-free survival (rPFS) was 49.8 months in the enzalutamide arm, compared to 38.9 months in the placebo arm.⁸ Notably, prespecified subgroup analyses suggested that enzalutamide induced more desirable survival outcomes across patients with low disease volume (HR=0.25; 95% CI: 0.14-0.46), high disease volume (HR=0.43; 95% CI: 0.33-0.57), no prior docetaxel therapy (HR=0.37; 95% CI: 0.28-0.49) or prior docetaxel therapy (HR=0.52; 95% CI: 0.30-0.89) (figure 2).⁷

In addition to reducing the risk of radiographic progression or death, enzalutamide + ADT also significantly reduced the risk of PSA progression (HR=0.28; 95% CI: 0.22-0.35).⁸ The addition of enzalutamide also offered a prolonged time to initiation of new antineoplastic therapy (HR=0.38; 95% CI: 0.31-0.48), first symptomatic skeletal event (HR=0.49; 95% CI: 0.37-0.65), and castration resistance (HR=0.39; 95% CI: 0.33-0.47).⁸ The final prespecified OS analysis of the ARCHES trial further established that the combination of enzalutamide and ADT facilitated significantly longer survival when compared to placebo (HR=0.66; 95% CI: 0.53-0.81; p<0.0001), where the 4-year OS rate of the enzalutamide arm was 71% compared to 57% in the placebo arm.⁸ Moreover, there was no significant difference in the risk of deterioration of urinary symptoms or QoL between the two arms, indicating that the addition of enzalutamide to ADT did not negatively impact patient-reported outcomes.⁷

In terms of safety, enzalutamide + ADT was shown to be welltolerated among the study population, where the incidence of treatment-emergent adverse events was consistent with the primary analysis, and no new safety signals were identified.⁸

Conclusion

Selecting the appropriate treatment for individuals with mHSPC involves navigating various clinical and patient-specific factors.^3-6 The data from the ARCHES trial demonstrated that doublet therapy with enzalutamide + ADT is an effective option for patients, irrespective of disease volume and prior chemotherapy.⁷ Furthermore, this combination provides a well-balanced safety profile and durable maintenance of high QoL over time, as illustrated in Dr. Lam's case sharing. Thus, enzalutamide in combination with ADT serves as a reliable solution that simultaneously maximizes disease control and satisfies patient preferences.⁷

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