Adding an androgen-receptor inhibitor to docetaxel and ADT in patients with mHSPC

Case 1: Triplet therapy in a patient with mHSPC and multiple comorbidities
A 68-year-old male patient presented with bone pain at multiple sites in November 2022. He did not have any other symptoms. He had hypertension and type 2 diabetes mellitus (T2DM), which were well controlled with amlodipine besylate 5 mg BID and metformin 1 g BID, respectively. He was generally well and had a baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0.

Initial examinations by a general practitioner showed elevated prostate-specific antigen (PSA) level of 80 ng/mL. Whole-body prostate-specific membrane antigen (PSMA) PET-CT scan showed uptake in the prostate, multiple lymph nodes (LNs) and bony metastases, including the left lower cervical LNs, pelvic bone and LNs, and in the glenoid region. (Figure 1)

Prostate biopsy confirmed adenocarcinoma with a Gleason score of 8 (4+4; Grade Group, 4). After further investigations, the patient was diagnosed with high-risk metastatic hormone-sensitive prostate cancer (mHSPC).¹

Treatment and response
On 4 January 2023, the patient started androgen deprivation therapy (ADT) with a luteinizing hormone–releasing hormone (LHRH) agonist, subcutaneous leuprorelin 11.25 mg administered Q3M, plus oral bicalutamide 50 mg QD coverage in the first week. On 9 January 2023, he started chemotherapy with intravenous (IV) infusions of docetaxel administered at 75 mg/m² Q3W for six cycles, alongside an oral androgen receptor inhibitor (ARI), darolutamide at 600 mg BID, at which point bicalutamide was stopped. He also received prophylaxis with granulocyte colony–stimulating factor (GCSF) to reduce the risk of developing neutropenia, which is a common adverse event (AE) associated with docetaxel.^2,3 The patient responded well and rapidly to this regimen. After the fifth cycle of docetaxel (March 2023), his PSA level dropped to <0.01 ng/mL. He completed the final sixth cycle of docetaxel on 24 April 2023 and continued treatment with leuprorelin and darolutamide.

In May 2023, follow-up PET-CT scan showed markedly reduced fluorodeoxyglucose (FDG) uptake in the prostate gland lesion as well as resolution of all metastatic bone lesions and LNs. (Figure 2) As mild FDG uptake persisted in the prostate tumour bed, the patient was given external radiotherapy (70 Gy in 35 fractions) in June–July 2023 to ensure better local control.

Treatment with leuprorelin, docetaxel and darolutamide was well tolerated. The patient reported some fatigue, finger numbness, hair loss and reduced appetite, all of which were mild. Despite taking concomitant medications for hypertension and T2DM, the patient did not require any treatment delays or dose reductions. Last seen in October 2023, he has remained asymptomatic and maintained an ECOG PS of 0 throughout treatment. His PSA level had remained at <0.01 ng/mL since dropping to that level in March 2023. The patient will continue to receive darolutamide and leuprorelin until disease progression or treatment intolerance. 

A 65-year-old male patient was diagnosed with prostate cancer in October 2022 after a routine checkup in a public hospital. He did not have any symptoms and was otherwise healthy, with a baseline ECOG PS of 0.

Prostate biopsy revealed adenocarcinoma, while other assessments showed a baseline Gleason score of 6 (3+3; Grade Group, 1) and a PSA level of 12 ng/mL. Based on the initial findings, he was assessed to have favourable intermediate-risk disease and was initially managed with active surveillance with PSA level monitoring and serial PET-CT scans.

In February 2023, PET-CT scan showed disease progression based on multiple metastatic lesions in the pelvic LNs and ribs. He sought consultation at our clinic in March 2023 and was diagnosed with mHSPC.

Treatment and response
The patient agreed to start docetaxel at 90 percent of the recommended dose (67.5 mg/m² Q3W via IV infusion for six cycles) due to personal concerns regarding potential AEs associated with chemotherapy, plus leuprorelin (11.25 mg Q3M via intramuscular [IM] injection) and darolutamide (600 mg BID, oral). He was given prophylactic GCSF to minimize the risk of neutropenia. The patient completed the last cycle of docetaxel in August 2023.

Overall, the patient tolerated the treatment well. He experienced grade 4 alopecia and grade 1 fatigue and peripheral neuropathy, which were attributed to docetaxel. However, these did not interfere with his quality of life (QoL). He remained active with ECOG PS of 0 while on treatment.

The patient continues to respond well to treatment. Last tested on 16 October 2023, his PSA level was 0.08 ng/mL. Except for the reported chemotherapy-related AEs, he remained asymptomatic, with no signs of disease progression, and continued to play tennis every day. The patient is expected to continue treatment with leuprorelin and darolutamide until disease progression or intolerance.

Discussion
Prostate cancer is diagnosed and assigned a risk category on the basis of symptoms, clinical features, PSA testing, and imaging. Patients with high-risk disease, such as our first patient, are treated immediately, while patients in a lower risk category, such as the patient in case 2, may undergo active surveillance with rigorous monitoring, which is intended to minimize overtreatment.¹

As there is currently no population-based screening for prostate cancer in Hong Kong, a proportion of patients present with symptomatic metastatic disease, such as our patient in case 1.^4,5 Routine medical check-ups in the primary care setting may help early detection, which was true for our second patient.

Active surveillance can be offered to eligible patients (eg, those with very-low-risk to favourable intermediate-risk disease and life expectancy >10 years) to safely delay treatment for several years or possibly avoid it entirely. This approach is aimed at maintaining QoL in the near term by virtue of eliminating the risk of AEs associated with prostate cancer treatment.¹ Importantly, active surveillance should only be offered to eligible patients on the basis of thorough clinical assessment, so as to avoid missing opportunities for early treatment in patients at high risk of progression.

Our second case was initially categorized as having favourable intermediate-risk disease based on PSA level and biopsy results alone, without baseline imaging studies. Nevertheless, despite the 5-month delay in initiating treatment, he still achieved favourable results with ADT, chemotherapy with docetaxel, and hormonal therapy with darolutamide.¹ This regimen is given a Category 1 recommendation in the National Comprehensive Cancer Network (NCCN) guidelines for patients with high-volume disease (eg, multiple metastases) who are fit for chemotherapy, like both of our patients who had ECOG PS of 0, and is listed as one of the preferred options in the NCCN guidelines.¹

Initially indicated for adult patients with nonmetastatic HSPC (nmHSPC) who are at high risk of developing metastatic disease, darolutamide is a recent addition to the treatment armamentarium for mHSPC. Its approval for mHSPC is based on positive results of the international, randomized, double-blind, placebo-controlled, phase III ARASENS (ODM-201 in Addition to Standard ADT and Docetaxel in Metastatic Castration Sensitive Prostate Cancer) trial, which compared overall survival (OS) of patients with mHSPC who received a combination of darolutamide (600 mg BID), ADT and docetaxel vs placebo, ADT and docetaxel.^1,6,7

At the primary analysis (n=1,306) data cut-off, the risk of death was 32.5 percent lower in the darolutamide vs placebo group (hazard ratio [HR], 0.68; 95 percent confidence interval [CI], 0.57–0.80; p<0.001). (Figure 3) At 4 years, the OS rate was 62.7 percent in the darolutamide group vs 50.4 percent in the placebo group. According to ARASENS investigators, these results provide clear and compelling evidence that OS was significantly longer among patients who received combination therapy with darolutamide, ADT and docetaxel vs those who received ADT and docetaxel alone.

Key secondary endpoints of ARASENS were also in favour of the darolutamide group, which demonstrated significantly longer time to castration-resistant prostate cancer (HR, 0.36; 95 percent CI, 0.30–0.42; p<0.001) and time to pain progression (HR, 0.79; 95 percent CI, 0.66–0.95; p<0.001).⁷ (Figure 4) Time to castration-resistant disease is particularly important, since patients whose cancer remains hormone-sensitive for longer are likely to achieve more favourable OS, which was observed in the ARASENS trial.^7,8

In addition, darolutamide was associated with consistent benefits across different prespecified subgroups, including patients with high-volume and high-risk/low-risk mHSPC.^7,9

The frequency of AEs in ARASENS was similar in both groups. Importantly, the incidence of most common AEs (occurring in ≥10 percent of patients) peaked during treatment with docetaxel in both groups, implying that these AEs were likely related to docetaxel. The overall frequency of grade 3/4 AEs was 66.1 percent in the darolutamide group vs 63.5 percent in the placebo group, with neutropenia being the most common grade 3/4 AE (33.7 percent and 34.2 percent).^7,9 In our patients, the use of GCSF prophylaxis effectively prevented severe neutropenia.

Darolutamide is a structurally distinct ARI with low blood-brain barrier penetration and limited potential for clinically relevant drug-drug interactions.^3,7 This was especially important for our patient in the first case, who was receiving comedication for his comorbidities but did not require any dose adjustments or treatment interruptions while on darolutamide. Apart from hypersensitivity to the active substance or any of the excipients, there are no absolute contraindications for darolutamide.³

In our experience, the ARASENS regimen improves outcomes in mHSPC as it allows men to benefit from chemotherapy while reducing the risk of potential AEs due to fewer cycles of docetaxel (ie, six cycles in combination with ADT and darolutamide vs 10 cycles in previous regimens).¹ We have also observed early response to treatment, with reduction in PSA levels occurring in less than 1–2 months after starting darolutamide. In both of our patients, PSA levels have remained <1 ng/mL during treatment with ADT plus darolutamide, with no signs of disease progression observed in either case and documented resolution of metastatic lesions achieved in case 1.

In summary, our patients’ positive experience with ADT plus docetaxel and darolutamide is consistent with the results of ARASENS, supporting the use of this triplet therapy regimen in chemotherapy-eligible patients with mHSPC.