Improvements in PSA, anaemia and performance status with ADT plus ARPI in a patient with mHSPC

History and presentation 
A 71-year-old male ex-smoker and non-drinker presented with bone pain and back pain in March 2024. He had a past history of advanced squamous-cell carcinoma of the tongue that was managed with sur­gery and adjuvant chemoradiation in 2018. At presentation, his haemoglo­bin (Hb) level was 6.3 g/dL, indicating severe anaemia. He also had a raised alkaline phosphatase (ALP) level and a highly elevated prostate-specific antigen (PSA) level of 3,700 ng/mL.

An MRI of the spine did not show spinal cord compression. X-ray and FDG PET-CT imaging detected mul­tiple bone metastases in the axial skeleton along with bone sclerosis, but no visceral metastases. Given the elevated PSA level and high volume of metastatic tumour burden, meta­static prostate cancer was suspect­ed. Subsequently, a transperineal ultrasound-guided prostate biopsy (TPUS) confirmed adenocarcinoma of the prostate with an International So­ciety of Urological Pathology (ISUP) grade group of 5.

When seen in May 2024, the pa­tient appeared pale and had a Hb lev­el of about 6 g/dL. His body weight was only 42 kg and Eastern Coop­erative Oncology Group performance status (ECOG PS) was 2. He also had an enlarged prostate because of the primary tumour, which led to urinary obstruction.

Treatment and response
A doublet regimen of degarelix (androgen depravation therapy [ADT]) and apalutamide (an androgen re­ceptor pathway inhibitor [ARPI]) was initiated in May 2024. Subsequently, the ADT component was switched to 3-monthly goserelin in June 2024.

The patient responded well to treatment with a reduction in PSA lev­el to 50 ng/mL in July 2024. Despite this drastic drop in PSA, his lower uri­nary tract symptoms persisted. Sim­ple palliative radiotherapy (21 Gy in 3 fractions over 1 week) was given to the prostate in July 2024, which alle­viated his symptoms.

The patient was last seen in Sep­tember 2024, 6 months after starting ADT plus apalutamide. Notably, his Hb level increased steadily over the 6 months to 9.5 g/dL, and his ECOG PS improved to 1. He gained about 1–2 kg of body weight, which is rea­sonable given his poor oral intake due to previous chemoradiation ther­apy to the tongue. So far, he toler­ated the treatment very well without any adverse effects.

Treatment with ADT plus apalut­amide is planned to continue until disease progression. In the mean­time, the patient is being followed up every 2 months.

Discussion
Currently, there is no central­ized prostate cancer screening pro­gramme in Hong Kong. As a result, a majority of cases present at an advanced stage, as did our patient who had multiple bone metasta­ses, severe anaemia and bone pain caused by marrow infiltration.¹ Al­though such high-volume metastatic hormone-sensitive prostate cancer (mHSPC) is considered incurable and has a poor prognosis, recent advanc­es in systemic therapy have demon­strated survival benefits with early in­tensification of ADT and the addition of an ARPI (+/- docetaxel).^2,3

According to international clinical practice guidelines, the current stan­dard of care for mHSPC regardless of disease volume is doublet therapy (ADT plus apalutamide/abiraterone/ enzalutamide), while the standard of care for fit patients with high-vol­ume disease is triplet therapy (ADT plus docetaxel plus abiraterone/ darolutamide).^4,5 To optimize clinical outcomes, treatment intensification with ARPIs must be implemented early, before castration resistance develops.

Choice of doublet or triplet first-line treatment for individual patients is guided by volume of disease, timing of metastasis detection and patient-specific factors, such as age and comorbidities.^2,4 We did not pur­sue triplet therapy for this patient as he had impaired bone marrow func­tion and a borderline PS (partly due to previous chemotherapy for cancer of the tongue) at presentation. There­fore, doublet therapy with ADT plus apalutamide was chosen. In Hong Kong, use of apalutamide in the high-volume mHSPC setting is sup­ported by the Samaritan Fund.⁶

In our clinical experience, apalut­amide is generally well tolerated. Fa­tigue is relatively mild, does not im­pact daily living, and can be managed with exercise and change in diet. In fact, our patient became more ener­getic after starting apalutamide, likely due to a reduction in bone metasta­ses and subsequent improvement in bone marrow function, as evidenced by an increase in his Hb level.

In the phase III, randomized, double-blind, placebo-controlled TITAN trial in patients with mHSPC (n=1,052), the addition of apalut­amide to ADT significantly improved overall survival (adjusted hazard ratio [HR], 0.52; 95 percent confidence interval [CI], 0.42–0.64; p<0.0001) and radiographic progression-free survival (HR, 0.48; 95 percent CI, 0.39–0.60; p<0.001) vs ADT alone, whilst maintaining health-related quality of life (HRQoL). According to TITAN data, patients’ experience of pain and fatigue (intensity and inter­ference) did not differ between the apalutamide and placebo groups for the duration of treatment.^7-9

A post hoc analysis of patient-reported outcomes (PROs: Func­tional Assessment of Cancer Therapy-Prostate [FACT-P], Brief Pain Inventory-Short Form [BPI-SF], Brief Fatigue Inventory [BFI]) from TITAN showed that apalutamide-treated patients who, like our case, achieved a rapid and deep PSA decline (≥90 percent decline or PSA ≤0.2 ng/mL) at 3 months had prolonged preserva­tion of HRQoL (as per total FACT-P) and physical well-being, as well as less pain and fatigue than those who did not.¹⁰ (Figure)

Whilst PSA is a useful tumour biomarker, other parameters, such as ALP, bone marrow function, and radiological evidence of progression, should also be considered when evaluating treatment response. Our patient experienced improvements in anaemia and PS after initiating apa­lutamide, implying improved HRQoL, which was reflected in his ECOG PS improving from 2 to 1 over the course of treatment.

Apalutamide is effective in a broad range of patients with mHSPC. In TITAN, all prognostic subgroups derived benefit from apalutamide regardless of disease volume, num­ber of metastases and synchronous/ metachronous metastasis at presen­tation.¹¹

Apalutamide is a strong inducer of CYP3A4 and is primarily metab­olized by CYP2C8 and CYP3A4.¹² Co-administration of apalutamide with modulators of these enzymes may result in drug-drug interactions, which are common across the entire ARPI drug class.¹³ Therefore, it is im­portant to continuously review con­comitant medications when a patient is receiving apalutamide.

In conclusion, ARPIs are most effective when used early in mHSPC treatment before development of castration resistance. Our patient presented with high-volume disease and severe anaemia. After being put on ADT plus apalutamide, he had a deep PSA response and an improved HRQoL.