CASE REVIEW

Enzalutamide improves overall survival and delays metastasis in patients with nonmetastatic, castration-resistant prostate cancer: A local case review

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Dr. Chiu, Ka-Fung Peter

Associate Professor,
Department of Surgery,
The Chinese University of Hong Kong

Based on the Prostate Cancer Working Group (PCWG) 3 consensus, prostate cancer patients are considered castration-resistant when a minimum rise of 2ng/mL in prostate-specific antigen (PSA) level is observed after androgen depletion therapy (ADT).1 Previously, castration-resistant prostate cancer patients without confirmed metastases, i.e. nonmetastatic (nmCRPC), would be subjected to the continuation of ADT despite disease progression.2 The recent phase 3 PROSPER clinical trial, however, illustrated that enzalutamide plus ADT can significantly extend overall survival (OS) and metastasis-free survival (MFS), and postpone the progression of pain and symptoms in nmCRPC patients.3-5 A local case of nmCRPC patient treated with enzalutamide in addition to ADT is described.

Background

In Hong Kong, prostate cancer is the third most common cancer in men with a gradually increasing age-standardized incidence rate.6 After treating with standard of care ADT, some prostate cancer patients would experience a rising PSA level and be classified as progression into castration-resistant disease. Without additional treatment, the disease would invariably progress to metastatic status with bone being the most common site of metastasis. Bone pain and pathological fracture may occur in cases with bone metastasis.7

The recently updated findings from the phase 3 PROSPER trial demonstrated that enzalutamide plus ADT could provide OS and metastasis-free survival benefits to patients with nmCRPC.3-5 This new evidence enables physicians to extend the therapeutic potential of enzalutamide to a wider range of prostate cancer patients and allows a more active approach towards nmCRPC. To demonstrate the clinical use of enzalutamide, Dr. Chiu shared a case of nmCRPC being treated with enzalutamide with excellent disease control.

Case report

In 2010, a 57-year-old man was diagnosed with prostate cancer with an initial presentation of mild urinary hesitancy and mild pain at the pelvis. The patient’s PSA level was at an astounding level of 3,798ng/ml and prompted the postulation of metastatic prostate cancer. Biopsy later confirmed the diagnosis of high grade prostate cancer, computed tomography (CT) scan and bone scan showed no sign of metastasis.

In view of his sky-high PSA level, the patient was treated as a metastatic patient and was given injectable luteinizing hormone releasing hormone (LHRH) agonist. After 6 months of treatment, the patient’s PSA level was reduced by more than 90% to 12ng/ml. However, after a year of ADT, his PSA level has rebounded to 30ng/ml without metastasis on repeated imaging. Radiotherapy to prostate was done in 2012. His PSA level maintained at a low level of 1.5ng/ml until 2016. Afterward, the patient experienced an increase in PSA level with a PSA doubling time of 6-7 months. He remained asymptomatic and repeated imaging confirmed nonmetastatic status. The patient was recruited in the PROSPER trial and being treated with enzalutamide.

Enzalutamide was started in February 2017 in addition to ongoing ADT. After a few months of treatment, his PSA level dropped to an undetectable level until his latest follow-up visit in August 2020 (Figure 1). The patient reported mild (grade 1) fatigue during treatment that did not interfere with his daily activities.

Discussion

PROSPER was a phase 3, international, double-blinded, randomized, placebo-controlled trial evaluating the efficacy of enzalutamide plus ADT in nmCRPC patients.3 For patients in the enzalutamide arm, the median metastatic-free survival (MFS) was 36.6 months, which was 21.9 months longer than those receiving ADT plus placebo (HR=0.29; 95% CI: 0.24-0.35; p<0.001) (Figure 2).4 Among 6 enrolled nmCRPC patients receiving enzalutamide at one local clinical trial site in Hong Kong, only 2 patients experienced PSA progression and only 1 patient progressed to metastasis at a median follow-up of 3 years.

Patient-reported outcomes of the PROSPER trial also illustrated a significant difference in pain progression and health-related quality of life between patients assigned to different groups.5 Patients on the enzalutamide arm had a significantly better health-related quality of life compared with placebo plus ADT (HR=0.83; 95% CI: 0.69-0.99; p=0.037).5 Comparing to patients on ADT alone, patients receiving the combination of ADT and enzalutamide had a longer time to pain progression (HR=0.75; 95% CI: 0.57-0.97; p=0.028).5

Most notably, the recent findings of the PROSPER trial demonstrated a statistically significant improvement in OS with enzalutamide.3 The median OS was 67.0 months in patients receiving enzalutamide which was 10.7 months longer than those in the placebo group (HR=0.73; 95% CI: 0.61-0.89; p=0.001) (Figure 3).3 Dr. Chiu stated, “These findings support the use of enzalutamide in nonmetastatic castration-resistant prostate cancer patients to improve OS, delay progression, and alleviate the burden of pain and symptom progression.”

After the disease progressed to metastatic castration-resistant state, chemotherapy can be offered. However, a recent global study illustrated that Asian males with metastatic disease were more likely to experience adverse events than their Caucasian counterpart during chemotherapy.8 Earlier intervention in nmCRPC patients can delay the time to cytotoxic chemotherapy.

Based on local experience, enzalutamide is usually well tolerated in nmCRPC patients. Severe adverse events and discontinuation due to adverse events related to enzalutamide are rare. With the PROSPER trial demonstrating the effectiveness of enzalutamide in nmCRPC patients in addition to those with metastatic diseases, the use of enzalutamide can be extended to nonmetastatic patients with PSA doubling time of 10 months or less to prolong survival and improve quality of life.9,10

Conclusion         

The PROSPER trial showed that nmCRPC patients with rapidly rising PSA level could benefit from enzalutamide in terms of overall survival, metastasis-free survival, and delayed symptom progression. Local experience illustrated that enzalutamide was effective and well-tolerated in Chinese patients with nmCRPC.

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