History, presentation and initial treatment
A 70-year-old male was diagnosed with prostate cancer (PC) after presenting with increased urinary frequency and an elevated prostate-specific antigen (PSA) level of 71 ng/mL in October 2022. (Figure) MRI revealed a 3 cm left prostatic lesion without pelvic lymph node involvement or bone metastases, with possible extraprostatic extension and seminal vesicle invasion. Transperineal ultrasound-guided prostate biopsy confirmed prostatic adenocarcinoma in 8 out of 12 cores, with a Gleason score of 4 + 3.
In January 2023, a prostate-specific membrane antigen (PSMA) PET-CT scan revealed multiple bone and lymph node metastases, consistent with high-risk, high-volume metastatic hormone-sensitive PC (mHSPC).
The patient had several comorbidities. He received a renal transplant in 2004, with ongoing everolimus, low-dose prednisolone and mycophenolate mofetil maintenance. He had a minor stroke in 2009. His atrial fibrillation, hypertension and hyperlipidaemia were managed with edoxaban, metoprolol, losartan and rosuvastatin. His baseline Eastern Cooperative Oncology Group performance status (ECOG PS) was 1.
The patient started androgen deprivation therapy (ADT) for mHSPC in January 2023. He was treated with monthly injections of a gonadotropin-releasing hormone (GnRH) antagonist, degarelix. By early March 2023, his PSA decreased to 3.57 ng/mL. (Figure) He was then referred to our hospital for further management.
Treatment with apalutamide and response
The patient started treatment with the oral androgen receptor pathway inhibitor (ARPI), apalutamide, at 240 mg QD in early March 2023. By late March 2023, his PSA dropped to 0.93 ng/mL.
In view of the likely drug–drug interactions, everolimus dose had to be increased to be maintained at an effective level. This, however, led to proteinuria, and everolimus was replaced with cyclosporine.1,2 The patient’s antihypertensive medication dosage was increased to optimize blood pressure control.
He developed generalized grade 2 pruritic eczematous rash. Initial antihistamines and topical agents were insufficient, prompting apalutamide dose reduction to 180 mg in May 2023, and then to 120 mg QD in June 2023. Combined with topical steroids, the patient’s rash fully resolved, allowing apalutamide therapy to continue at 120 mg QD.
In July 2023, for the patient’s convenience, ADT was switched from degarelix to leuprorelin, a GnRH agonist administered subcutaneously every 6 months. The patient experienced no notable adverse events (AEs) with apalutamide 120 mg QD. By September 2023, his PSA level had declined to below the hospital laboratory’s assay detection threshold (ie, ≤0.03 ng/mL). (Figure)
Last seen in September 2025, the patient remained clinically stable with an ECOG PS of 1 and undetectable PSA levels.
Discussion
The preferred regimen for elderly mHSPC patients with multiple comorbidities, such as the present case, is doublet therapy with ADT plus an ARPI.3 The Hospital Authority currently provides financial assistance for apalutamide and enzalutamide in mHSPC setting.4 Abiraterone is also an option for doublet therapy in this setting. Apalutamide was chosen for our patient to reduce the risk of central nervous system AEs associated with enzalutamide, in view of his prior stroke.5,6
Results from the phase III, double-blind, placebo-controlled TITAN trial (n=1,052) support treatment intensification by adding apalutamide to ADT in patients with mHSPC. Patients treated with apalutamide plus ADT had a higher 24-month rate of radiographic progression-free survival (PFS) (68.2 vs 47.5 percent; hazard ratio [HR], 0.48; 95 percent confidence interval [CI], 0.39–0.60; p<0.001) and longer overall survival (OS) (median, not reached vs 52.2 months; HR, 0.52; 95 percent CI, 0.42–0.64; p<0.0001) vs those treated with ADT alone.7,8
Frequencies of grade 3 or 4 AEs (42.2 vs 40.8 percent) and serious AEs (19.8 vs 20.3 percent) did not differ substantially between the apalutamide and placebo groups. Rash of any grade was more common in the apalutamide group (27.1 vs 8.5 percent). However, most cases were of grade 1 or 2 and could be managed with apalutamide dose interruptions or adjustments, and antihistamines and topical corticosteroids, which is similar to our patient’s experience, whose apalutamide dose was eventually halved. Of note, in our patient’s case, dose reduction did not compromise the durable PSA suppression by apalutamide.7
TITAN’s post hoc analysis showed that patients achieving ultra-low PSA levels at 3–6 months derived the greatest clinical benefit.9,10 By 3 months, a greater proportion of patients who received ADT plus apalutamide achieved an ultra-low PSA level of 0.2 to >0.02 ng/mL (UL1) and ≤0.02 ng/mL (UL2) (38 and 23 percent, respectively) vs those who received ADT alone (15 and 5 percent, respectively). Patients who achieved UL2 at 3 months had the greatest clinical benefit in terms of radiographic PFS (HR, 0.28; 95 percent CI, 0.14–0.54), OS (HR, 0.24; 95 percent CI, 0.13–0.43), time to castration resistance (HR, 0.2; 95 percent CI, 0.11–0.38), and time to PSA progression (HR, 0.11; 95 percent CI, 0.04–0.27) vs those with PSA >0.2 ng/mL at 3 months (all p<0.001). Although less pronounced, a similar association was observed for UL1, and similar findings were reported at 6 months.10
The IRONMAN registry (n=1,288) further validated absolute PSA at 6–12 months as a robust real-world prognostic marker. mHSPC patients with UL2 and UL1 at 12 months had significantly better 3-year OS and PFS rates than patients with PSA >0.2 ng/mL (3-year OS rate: UL2, 92.7 percent; UL1, 80.0 percent; PSA >0.2 ng/mL, 45.3 percent; 3-year PFS rate: UL2, 93.0 percent; UL1, 72.9 percent; PSA >0.2 ng/mL, 36.7 percent).11,12
Similarly, the OASIS Japan cohort (n=15,797) found that upfront apalutamide plus ADT resulted in faster, deeper PSA responses and longer survival than traditional combined androgen blockade (CAB) or ADT alone. Results showed that OS and castration resistance–free survival were significantly longer in patients initially treated with apalutamide plus ADT vs CAB or ADT (p<0.0001 for both comparisons). Significantly more patients who started with apalutamide plus ADT also had undetectable PSA levels (≤0.2 ng/ mL) at 3 months vs those who received CAB or ADT (p<0.0001).13
In summary, our patient’s experience highlights the benefits of adding apalutamide to ADT for deep, rapid and sustained PSA reduction, and aligns with results from clinical and real-world studies. His PSA became undetectable (≤0.03 ng/mL) within 6 months of starting apalutamide and remained at this level over 2 years of treatment, even following dose reductions.
