Second-generation antiandrogen in an elderly patient with high-volume mCSPC and multiple comorbidities

Presentation and management
A 75-year-old male presented with frequent urination in January 2023. His prostate-specific antigen (PSA) level was above normal at 54.2 ng/mL. Prostate biopsy yielded a Glea­son score of 4 + 3. Prostate-specific membrane antigen (PSMA) PET-CT scan showed multiple bone metas­tases, with left supraclavicular lymph node (LN) and right external iliac LN uptake. The patient was diag­nosed with high-volume metastatic castration-sensitive prostate cancer (mCSPC).

The patient's Eastern Cooper­ative Oncology Group (ECOG) per­formance status (PS) score was 2. He had a history of minor stroke and benign gastrointestinal stromal tu­mour. At diagnosis, he had multiple comorbidities requiring various come­dications, including metoprolol tartrate 25 mg BID for hypertension, rosuvas­tatin 5 mg QD for hyperlipidaemia, and edoxaban 30 mg QD for atrial fibril­lation. He had also undergone renal transplant due to end-stage kidney disease and was on cyclosporine A (150 mg OM and 125 mg PM), which replaced everolimus due to drug-drug interactions (DDIs).

In January 2023, the patient com­menced androgen deprivation ther­apy (ADT) with degarelix Q1M, which was switched to leuprorelin Q3M in February 2023. A second-generation androgen receptor inhibitor (ARI), apalutamide (240 mg), was added in February 2023. One month after starting apalutamide, the patient’s uri­nary frequency improved along with a substantial decrease in PSA level from 54.2 ng/mL to 3.57 ng/mL.

In May 2023, the patient began to experience ankle oedema and pru­ritus, with grade 2 eczematous rash on limbs and trunk. He was treated with loratadine and antipruritic cream, and apalutamide’s daily dose was re­duced to 180 mg. Although his an­kle oedema improved, the rash per­sisted until July 2023. The dose of apalutamide was further reduced to 120 mg daily and he was given a ste­roid cream and another oral antihista­mine (chlorphenamine), after which the rash gradually improved.

Notably, despite two dose reduc­tions, the patient’s PSA level con­tinued to drop consistently: from 3.57 ng/mL to 0.14 ng/mL after the first reduction and from 0.07 ng/mL to 0.03 ng/mL after the second.

As of October 2023, the patient re­mained on leuprorelin and apalutamide 120 mg daily, tolerating his treatment well.

Discussion
According to European Associ­ation of Urology’s guidelines, dou­blet therapy with ADT and an ARI is a recommended first-line option for mCSPC.¹

When choosing between avail­able ARIs for our patient, we consid­ered their ability to achieve ≥90 per­cent reduction in PSA (PSA90) within 3 months, which is associated with favourable prognosis in mCSPC.² In a real-world study comprising 351 patients with mCSPC, apalutamide was associated with higher rates of PSA90 (70.4 percent vs 62.5 percent; hazard ratio, 1.49; 95 percent confi­dence interval, 1.05–2.11; p=0.024) and a shorter median time to PSA90 response (3.1 months vs 5.2 months) vs enzalutamide.³ (Figure)

In addition, compared with en­zalutamide, apalutamide was asso­ciated with a longer time to develop­ment of castration resistance (CR), which is associated with poor prog­nosis in mCSPC.⁴ A retrospective, longitudinal cohort study of mCSPC patients (n=1,251) showed lower rates of CR progression at 12 months, 18 months and 24 months with apalut­amide vs enzalutamide (12.4 percent, 23.5 percent and 26.2 percent vs 23.5 percent, 28.8 percent and 36.3 per­cent, respectively) and higher rates of CR-free survival (82.6 percent, 70.1 percent and 67.6 percent vs 71.5 per­cent, 62.6 percent and 53.9 percent, respectively).⁵

Apalutamide is generally well tol­erated. The most common adverse events (AEs) of all grades reported in a randomized clinical trial were skin rash, fatigue, hypertension, and di­arrhoea (vs placebo: 28 percent vs 9 percent, 20 percent vs 17 per­cent, 18 percent vs 16 percent, and 9 percent vs 6 percent, respective­ly), but the majority of these events were of grade 1–2.⁶ Despite report­ing some AEs, patients in the ADT plus apalutamide arm of the phase III TITAN trial (n=1,052) maintained good health-related quality of life throughout the study (median follow-up, 44 months).⁷

In our practice, apalutamide-related skin reactions have not been encountered frequently and can gen­erally be managed with an oral anti­histamine and topical antipruritic and/or steroid cream. Haemoglobin level monitoring is advised for patients ex­periencing fatigue to eliminate possible ADT-related anaemia.⁸ Engaging in physical activity is also recommend­ed to increase stamina. Blood pres­sure (BP) monitoring is advised for early detection of ARI-associated hypertension that may require treat­ment.⁹ Patients are instructed to measure their BP at home daily as “white-coat hypertension” might be encountered at the clinic. Mild diar­rhoea is managed with antimotility medication. If mild AEs persist or in case of grade ≥3 AEs, apalutamide dose reduction or temporary suspen­sion may be necessary.

ARI-related falls and resulting frac­tures are of concern for elderly pa­tients, particularly those who are frail with ECOG PS score ≥2 or have co­morbidities, such as visual impairment or history of stroke. Patients and their social support should be assessed individually, with caution exercised, when prescribing these agents.¹⁰

DDIs should also be considered when prescribing ARIs. Concomitant use of apalutamide with medications primarily metabolized by CYP3A4, CYP2C19 or CYP2C9 can lower their concentration. If apalutamide is co-administered with an anticoagu­lant metabolized by CYP2C9, such as warfarin, patients’ clotting profile should be closely monitored. More­over, co-administration with a strong CYP2C8 or CYP3A4 inhibitor is pre­dicted to increase exposure to apa­lutamide. Although initial dose adjust­ment is not necessary, apalutamide’s dose may be reduced based on tolerability.¹⁰

While ADT and ARI can be initiat­ed at the same time, our patient was put on apalutamide 1 month after ADT initiation to allow a washout period for everolimus, a substrate of CYP3A4, to avoid potential DDIs.¹¹ In spite of this delay, his PSA level declined substan­tialy within a month of starting apa­lutamide. Furthermore, his PSA level continued to drop even following two apalutamide dose reductions necessi­tated by rash.

Most importantly, our elderly pa­tient with multiple comorbidities and concomitant medications remained asymptomatic with no sign of disease progression and maintained a good quality of life with ADT plus apalut­amide treatment.

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