First-line androgen receptor inhibitor plus low-dose prednisolone in a patient with mCRPC and comorbidities

Presentation, treatment and response
A 69-year-old male presented with lower limb weakness and urinary retention in February 2018 and was admitted to the orthopaedic ward. He had a history of hypertension and hyperlipidaemia, which were controlled with lisinopril and simvastatin, respectively.

MRI in February 2018 revealed spinal cord compression and multiple bone lesions, while a bone scan found multiple bone metastases in the thoracic vertebrae (T3, T5, T8–T12), lumbar vertebrae (L1–L5), pelvis and ribs. Laboratory assessments revealed elevated levels of prostate-specific antigen (PSA; 325 ng/mL) and alkaline phosphatase (ALP; 168 IU/L). Laminectomy was immediately performed for decompression, after which the patient recovered well. Radiotherapy plus hormone therapy with luteinizing hormone–releasing hormone (LHRH) injections (initially degarelix 240 mg QM, followed by 80 mg QM for 3 months and then leuprorelin 11.25 mg Q3M) were commenced simultaneously to control his prostate cancer, which resulted in PSA normalization in December 2018.

However, biochemical progression was noted approximately 4 years later (PSA level, 41 ng/mL). The patient also experienced lower back pain, requiring analgesic treatment (paracetamol 1,000 mg) and a cane as a walking aid (Eastern Cooperative Oncology Group performance status [ECOG PS], 1). Bone scan in May 2022 confirmed multiple bone metastases in the spine, pelvis and ribs, while blood tests revealed elevated ALP level (399 IU/L), leading to a diagnosis of metastatic castration-resistant prostate cancer (mCRPC). (Figure 1)

In May 2022, the patient was started on oral abiraterone acetate (AA; 1,000 mg QD), and low-dose prednisolone (P; 5 mg BID).¹ He achieved early treatment response, as evidenced by normalization of PSA level (5.9 ng/mL) after 1 month of treatment. In July 2022, his PSA level further dropped to 1.7 ng/mL, and he was able to walk unaided due to relieved lower back pain, which resulted in an improvement of ECOG PS from 1 to 0. Bone scan after 6 months of treatment showed that all bone metastases were either stable or improved. (Figure 1)

The patient tolerated treatment with AA + low-dose P well, without any adverse events (AEs). His blood pressure and lipid levels remained well controlled throughout treatment, without requiring adjustments to his baseline medications.

Last seen February 2023 (ie, after 9 months of treatment), the patient remained in good condition with good quality of life (QoL), low PSA level (0.08 ng/mL), and ECOG PS of 0.

Discussion
According to guidelines of the European Society for Medical Oncology, androgen receptor (AR) inhibitors (AA or enzalutamide [ENZA]) and docetaxel are recommended frontline treatment options for mCRPC patients (level of evidence, I; grade of recommendation, A).² As our patient developed castration resistance during Hong Kong’s fifth wave of COVID-19, an AR inhibitor was preferred over docetaxel to avoid neutropenia and in-hospital intravenous drug administration.^3-5

Based on our centre’s experience, frontline use of AA + low-dose P leads to rapid disease control. As demonstrated in our patient, frontline AA + low-dose P therapy resulted in rapid normalization of PSA level, resolution of lower back pain, and improvement in ECOG PS (from 1 to 0) within 1–2 months.^6,7

Long-term benefits of AA + low-dose P treatment were shown in the phase III COU-AA-302 trial, in which 1,088 chemotherapy-naïve mCRPC patients were randomized (1:1) to receive either AA (1,000 mg QD) + P (5 mg BID) or placebo + P. At a median follow-up of 49.2 months, AA + low-dose P demonstrated statistically significant improvements in overall survival (median, 34.7 months vs 30.3 months; hazard ratio [HR], 0.81; 95 percent confidence interval [CI], 0.70–0.93; p=0.0033) and time to opioid use for prostate cancer–related pain (median, 33.4 months vs 23.4 months; HR, 0.72; 95 percent CI, 0.61–0.85; p<0.0001) vs P alone.⁵

Furthermore, AA + low-dose P was associated with better patient-reported outcomes vs ENZA in mCRPC. The 12-month observational AQUARiUS trial showed that AA-treated patients experienced significantly less fatigue and cognitive impairment vs ENZA-treated patients (both p<0.05), and these differences were observed early within the first month of treatment.⁸

The addition of low-dose P to AA was safe and tolerable in mCRPC patients. Results of a pooled analysis of the COU-AA-301 and COU-AA-302 trials (n=2,267) showed a low incidence rate of corticosteroid-associated AEs (CA-AEs) with AA + low-dose P (any grades, 25.5 percent; grade ≥3, 5.0 percent). Notably, the incidence rate of CA-AEs remained low even with increased duration of exposure to low-dose P.⁹ In patients treated with AA, coadministration of low-dose P serves as a glucocorticoid replacement therapy, which helps reduce the incidence and severity of AEs arising from CYP17A1 inhibition with AA. As such, concurrent low-dose P is not a major safety concern in most mCRPC patients on AA.¹⁰ In our patient with hypertension and hyperlipidaemia, no AEs, including CA-AEs, were reported during 9 months of treatment with AA + low-dose P, nor did he require adjustments to his antihypertensive or antilipidaemic medications.

The decision to use frontline AA, and not ENZA, in our patient was based on results of a phase II, randomized, open-label crossover trial, which sought to determine the optimal sequence of AR inhibitors in mCRPC (ie, AA to ENZA [n=101], or ENZA to AA [n=101]). At a median follow-up of 22.8 months, the AA-to-ENZA sequence was associated with a significantly longer time to second PSA progression vs the ENZA-to-AA sequence (median, 19.3 months vs 15.2 months; HR, 0.66; 95 percent CI, 0.45–0.97; p=0.036).¹¹ PSA responses to second-line treatment were observed in 36 percent vs 4 percent of patients. Similarly, the Kyoto-Baltimore collaboration study (n=198) revealed that combined PSA progression–free survival (ie, the time from the start of the first AR inhibitor to PSA progression on the second AR inhibitor) was significantly longer with the AA-to-ENZA sequence (median, 455 days vs 296 days; HR, 0.56; 95 percent CI, 0.41–0.76; p<0.001) vs the ENZA-to-AA sequence. Results of these two studies support AA followed by ENZA as the optimal sequencing strategy in mCRPC.^11,12

In summary, the current case demonstrates that AA + low-dose P can be effectively and safely used in patients with mCRPC and comorbid hypertension and hyperlipidaemia in the first-line setting.