Use of an ARPI in combination with ADT in a patient with mHSPC
19 Dec 2024
byDr. Wai-Kit Ma, Specialist in Urology, Private practice, Hong Kong
History and presentation
A 74-year-old male presented with back pain, right hip pain, and right lower limb weakness in December 2023. He was a chronic smoker and had impaired fasting glucose that was controlled with diet. Workup in mainland China with CT scan revealed multiple osteolytic lesions in the pelvis and bony spine. Blood test showed elevated serum prostate-specific antigen (PSA) level >300 ng/mL. He was on etoricoxib and acetaminophen for analgesia.
The patient was then managed in Hong Kong, with a repeated serum PSA test showing a level of 484 ng/mL. A transperineal six-sector prostate biopsy was performed to determine the pathological grading.
Biopsy pathology showed presence of acinar adenocarcinoma in all sectors with cancer involvement ranging from 40 to 80 percent of biopsy cores in each sector. His highest Gleason score (GS) was 4+5, placing him in the high-risk category.
A prostate-specific membrane antigen (PSMA)–PET-CT scan detected diffuse cancer in the entire prostate gland, with a maximum standardized uptake value (SUVmax) of 23.6. The scan showed invasion of bilateral seminal vesicles and a right pelvic lymph node. There were also widespread bone metastases involving more than five spinal levels, the bony pelvis, bilateral clavicles, scapula, right humerus, and the right femoral neck. Based on these findings, his disease was classified as high-volume, high-risk, metastatic hormone-sensitive prostate cancer (mHSPC).
Despite the bone pain, the patient was fully ambulatory and required minimal assistance from family. His Eastern Cooperative Oncology Group performance status (ECOG PS) was 1.
Treatment and response
Androgen deprivation therapy (ADT) with monthly injections of degarelix, a gonadotropin-releasing hormone (GnRH) antagonist, was initiated on 11 December 2023. Given the potential risk of skeletal events with hormonal therapy and the presence of widespread bone metastases, denosumab (a bone-modifying agent) and daily oral supplements of calcium and vitamin D were also prescribed.
The patient did not want to add chemotherapy to his regimen. After discussion of clinical data, he opted for apalutamide, an oral androgen receptor pathway inhibitor (ARPI), which was initiated shortly after degarelix.
In January 2024, after just 1 month of treatment with ADT plus apalutamide, there was a significant drop in the patient’s PSA level to 6.46 ng/mL. In subsequent months, the PSA values continued to decline, reaching an undetectable level (<0.03 ng/mL) in May 2024. Since then, his PSA levels had remained undetectable until the last test in August 2024. (Figure)
The patient was last seen in September 2024. So far, he has tolerated the treatment very well and has not reported any adverse effects. His pain symptoms have improved by about 80 percent, reducing the need for analgesics. His ECOG status remains at 1 and he is maintaining a good quality of life. To minimize clinic visits, his monthly degarelix injections were replaced with 3-monthly injections of leuprorelin. The plan is to continue duplet therapy with ADT plus apalutamide, until disease progression or intolerance.
Discussion
Prostate cancer is the fourth leading cause of male cancer deaths in Hong Kong.1 Over half of local cases are diagnosed at advanced stage (3 and 4), which underscores the need for screening.2 Although there are currently no population-wide PSA screening programmes in Hong Kong, men >50 years of age can request a serum PSA test through their family physicians. It is also vital for healthcare professionals to recognize the importance of cut-off values and pursue further workup even if PSA levels are mildly elevated. Tests that are less invasive than a biopsy, such as the prostate health index (PHI) (for PSA 4–10 ng/mL) or MRI, can be performed as part of initial prostate cancer risk assessment. To note, ultrasound is not a good imaging modality for prostate cancer screening as up to 40 percent of prostate cancer lesions are isoechoic on conventional B-mode ultrasound.3
The current preferred regimen for mHSPC patients regardless of disease volume is doublet therapy (ADT plus apalutamide/abiraterone/enzalutamide), while the standard of care for fit patients with high-volume mHSPC is triplet therapy (ADT plus docetaxel plus abiraterone/darolutamide).4,5 Since ADT monotherapy is no longer recommended in the guidelines for treatment of mHSPC, and our patient refused treatment intensification with chemotherapy, he was given a doublet regimen consisting of ADT plus apalutamide.4
In the phase III, randomized, double-blind, placebo-controlled TITAN study involving 1,052 patients with mHSPC, the addition of apalutamide to ADT improved radiographic progression-free survival (rPFS rate at 24 months: 68.2 vs 47.5 percent; hazard ratio [HR], 0.48; 95 percent confidence interval [CI], 0.39–0.60; p<0.001) and overall survival (OS; median not reached vs 52.2 months; adjusted HR, 0.52; 95 percent CI, 0.42–0.64; p<0.0001) vs ADT alone.6,7 Notably, patients with rapid and deep PSA decline (≥90 percent PSA decline or PSA ≤0.2 ng/mL) at 3 months of apalutamide treatment had better clinical outcomes vs those without such decline.8
A post hoc analysis of TITAN further confirmed that patients with the deepest PSA decline on apalutamide derived the greatest benefit. Specifically, patients who achieved an ultra-low PSA level of ≤0.02 ng/ mL (UL2) had significantly longer rPFS (HR, 0.28; 95 percent CI, 0.14–0.54), OS (HR, 0.24; 95 percent CI, 0.13–0.43), and time to castration-resistant prostate cancer (HR, 0.2; 95 percent CI, 0.11–0.38) vs those who achieved PSA >0.2 ng/mL.9 A similar, but less pronounced, association was also observed for patients who achieved ultra-low PSA level of 0.2–>0.02 ng/mL (UL1). By 3 months, more patients achieved UL1 and UL2 PSA levels with apalutamide (38 and 23 percent, respectively) vs placebo (15 and 5 percent, respectively).9
In clinical trials of apalutamide, skin rash was the most common side effect, occurring in one quarter of treated patients.10 While our patient was not affected by it, in cases where it occurs, the rash is typically low-grade and can be easily managed with oral antihistamines and topical corticosteroids.
Apalutamide has favourable tolerability and requires less patient monitoring compared with other ARPIs available in Hong Kong.10-12 In our clinical experience, patients on apalutamide are less likely to have lower-limb oedema than enzalutamide-treated patients. In addition, we have noticed a lower level of fatigue with apalutamide. Most patients, like the one described above, are able to maintain a stable energy level and carry out their activities of daily living.
In conclusion, our patient’s case demonstrates a substantial and rapid PSA response to and very good tolerance of ADT plus apalutamide. In the TITAN trial, patients with a rapid and deep PSA decline to ultra-low levels derived the greatest benefit, including improved rPFS and OS. To induce such PSA responses in local patients, mHSPC treatment in Hong Kong should be brought in line with guideline-recommended standard of using at least a doublet regimen consisting of ADT plus ARPI in all eligible patients regardless of disease volume.4,5
