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Dr Margaret Shi, 02 Jan 2020

Tivozanib as third- or fourth-line therapy improves progression-free survival (PFS) compared with sorafenib in patients with metastatic renal cell carcinoma (mRCC) who have received ≥2 previous systemic treatments, according to results of the phase III, randomized, controlled TIVO-3 trial.

Management of metastatic castration-resistant prostate cancer with an androgen-receptor inhibitor

Dr. Kenneth Wong
Specialist in Clinical Oncology
Hong Kong
27 Nov 2019

History and presentation

A 79-year-old gentleman with a history of diabetes, hypertension, hyperlipidaemia, and vitamin B12 and folate deficiency first presented with acute retention of urine in February 2015. Transurethral resection of the prostate was done which revealed prostatic acinar adenocarcinoma with Gleason score of 5+4. The prostate-specific antigen (PSA) level was 261µg/L and 11C-acetate PET/CT scan showed distant lymph node and bone metastases.

Treatment and response

Androgen deprivation therapy (ADT) with degarelix was initiated in May 2015 upon diagnosis. Chemohormonal therapy with docetaxel was offered in view of extensive bone metastases, but it was declined by the patient due to concerns about treatment tolerability due to his advanced age. Treatment was switched to leuprorelin in February 2016 as patient preferred 3-monthly injections.

Enzalutamide (160mg daily) was added to existing treatment in December 2016 due to biochemical disease progression, i.e. the development of metastatic castration-resistant prostate cancer (mCRPC). (Figure) At that time, the patient had an ECOG performance status of 1 with complaints of mild bone pain. He responded well to enzalutamide treatment, as reflected by a decrease in PSA levels with no definite fluorodeoxyglucose-avid lesions shown on repeat PET/CT scan.

However, his PSA began to rise approximately 2 years after treatment initiation. (Figure) Treatment was therefore switched to abiraterone and prednisolone in March 2019. Despite this, his PSA continued to rise over the next few months, indicating inadequate response. Treatment with abiraterone and prednisolone was thus stopped in June 2019. The patient was not keen on starting radium-223 therapy and decided, considering his advanced age and worsening condition, to opt for best supportive care. The patient is currently alive with the disease, and is still on leuprorelin.

The patient was on enzalutamide 160mg continuously for nearly 26 months. During this period, he had good overall tolerance to enzalutamide without development of adverse reactions apart from grade 1/2 fatigue.

016mo

Discussion

The latest US National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Prostate Cancer recommended enzalutamide for treating chemotherapy-naïve patients with mCRPC.1

Enzalutamide is an orally available, non-steroidal, second-generation antiandrogen that acts on multiple steps in the androgen receptor (AR) signalling pathway that are essential for tumour growth and progression in CRPC. Enzalutamide binds to the AR with greater relative affinity than the first-generation antiandrogens such as bicalutamide, reduces the efficiency of AR nuclear translocation, and impairs both binding to androgen response elements in DNA and recruitment of coactivators. Unlike bicalutamide, enzalutamide lacks partial AR agonist activity.2

Our case is an elderly patient with multiple comorbidities who was mildly symptomatic from his metastases. Although initial ADT was effective in our patient, his disease progressed to CRPC within 1.5 years, requiring treatment with enzalutamide. Its use is supported by significant and clinically meaningful benefits demonstrated in clinical trials in men with chemotherapy-naïve mCRPC.

In the phase III PREVAIL trial, enzalutamide was shown to significantly improve, when compared with placebo, the rate of centrally-assessed radiographic progression-free survival (rPFS) at 12 months (65 percent vs 14 percent; hazard ratio [HR], 0.19; 95 percent confidence interval [CI], 0.15 to 0.23; p<0.001) and the overall survival (OS) after a median follow-up of 31 months in the extended analysis (35.3 months vs 31.3 months; HR, 0.77; 95 percent CI, 0.67 to 0.88; p=0.0002). Statistically significant (p<0.001) improvements were also observed in secondary endpoints: initiation of cytotoxic chemotherapy (HR, 0.35), time until decline in quality of life as measured on the Functional Assessment of Cancer Therapy-Prostate (FACT-P) scale (HR, 0.63), time until first skeletal-related event (HR, 0.72), time until PSA progression (HR, 0.17), percentage with PSA decline of at least 50 percent (78 percent vs 3 percent), and complete or partial soft-tissue response (59 percent vs 5 percent).3, 4

Results of a subgroup analysis of PREVAIL further supported the use of enzalutamide in elderly patients (aged ≥75 years). Specifically, median rPFS (not yet reached vs 3.7 months; HR, 0.17; 95 percent CI, 0.12 to 0.24; p<0.0001) and median OS (32.4 months vs 25.1 months; HR, 0.61; 95 percent CI, 0.47 to 0.79; p=0.0001) were significantly improved with enzalutamide. However, a higher incidence of falls was noted among elderly vs younger patients <75 years of age (13.8 percent vs 5.6 percent) and in elderly patients treated with enzalutamide vs those receiving placebo (19.2 percent vs 7.9 percent).5

Phase II trials have also demonstrated superiority of enzalutamide vs bicalutamide. For example, in the TERRAIN study, enzalutamide led to a significant improvement in PFS (median, 15.7 months vs 5.8 months; HR, 0.44; 95 CI, 0.34 to 0.57; p<0.0001) and rPFS (not reached vs 16.4 months; HR, 0.51; 95 CI, 0.36 to 0.74; p=0.0002) vs bicalutamide. The median time to a PSA progression event was also increased with enzalutamide (19.4 months vs 5.8 months; HR, 0.28; 95 CI, 0.20 to 0.39; p<0.0001).6 Similarly, in the STRIVE study which included both non-metastatic and metastatic CRPC patients, enzalutamide resulted in remarkable improvements in the median time to PSA progression (median, not reached vs 8.3 months; HR, 0.19; 95 CI, 0.14 to 0.26; p<0.001) and the proportion of patients with a ≥50 percent  PSA response (81 percent vs 31 percent; p<0.001) compared with bicalutamide.7

Treatment-associated fatigue, which was also reported by our patient, is a well-recognized adverse event (AE) of enzalutamide, occurring in 35.6 percent of patients in the PREVAIL trial and in 64.1 percent of patients in a real-world study conducted in Hong Kong.3,8 However, using enzalutamide in earlier lines of treatment was associated with improved PSA response rates as well as less fatigue in a real-world setting.8 In general, the benefits of enzalutamide can be achieved with a favourable safety profile, with the PREVAIL trial reporting a 9-month delay in the median time until the first grade ≥3 AE in the enzalutamide group.3

Conclusion

Our case illustrates the efficacy of enzalutamide after disease progression on ADT. In clinical trials, enzalutamide was superior to bicalutamide in terms of PFS and time to PSA progression.

In our patient, enzalutamide’s AE of fatigue was managed conservatively, with the risk of falls assessed regularly. He  received full-dose enzalutamide treatment throughout, with good tolerability given his advanced age.

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Most Read Articles
Dr Margaret Shi, 02 Jan 2020

Tivozanib as third- or fourth-line therapy improves progression-free survival (PFS) compared with sorafenib in patients with metastatic renal cell carcinoma (mRCC) who have received ≥2 previous systemic treatments, according to results of the phase III, randomized, controlled TIVO-3 trial.