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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.

Effective control of metastatic CRPC with an androgen-receptor inhibitor after inadequate response to two previous therapies

Dr. Siu Hong Lee
Specialist in Oncology
Hong Kong
10 Oct 2019
History and Presentation
A 65-year-old man with a history of type 2 diabetes mellitus and hepatitis B virus (HBV) infection first presented with back pain and mild lower urinary tract symptoms, including increased urgency and frequency of urination, in November  2017. Other than the presence of a hard prostate identified upon rectal examination and bone tenderness detected in the back and pelvis, there were no other significant physical findings. PET scan showed increased FDG uptake in the prostate and multiple bone metastases along the vertebral column and pelvic region. The patient was subsequently diagnosed with metastatic prostate cancer. Biopsy of the tumour revealed adenocarcinoma. The patient’s prostate-specific antigen (PSA) level was 500 ng/mL and Gleason score was 4+4.

Treatment and response
Luteinizing hormone-releasing hormone (LHRH) analogue therapy was initiated upon diagnosis. The patient responded well to treatment. His PSA level dropped to 3 ng/mL following 9 months of LHRH analogue therapy. The pain and lower urinary tract symptoms also resolved with treatment.

However, the patient’s PSA level began to rise about a year after treatment initiation, and bicalutamide was therefore added. In spite of this, his PSA levels continued to rise over the next 3 months, indicating inadequate response. The patient was then switched to enzalutamide in March 2019. His PSA levels have since dropped to <0.1 ng/mL and he has been tolerating the treatment well with minimal side effects.

Xtandi - case_for Dr Lee

Discussion
The latest European Society for Oncology (ESMO) clinical practice guidelines for prostate cancer and the US National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Prostate Cancer recommend enzalutamide for treating chemotherapy-naïve, metastatic castration-resistant prostate cancer (CRPC).1,2

Our case illustrates the efficacy of enzalutamide in metastatic CRPC after disease progression with initial androgen-deprivation hormonal therapy and subsequent nonsteroidal antiandrogen therapy with bicalutamide. Having taken into consideration the patient’s history, enzalutamide was chosen over other guideline-recommended treatment options as it does not require concurrent administration of corticosteroids, which may cause poor blood glucose control and HBV reactivation that would compromise cancer treatment.

Enzalutamide is an androgen-receptor inhibitor that binds to the androgen receptor in the same way as bicalutamide, but of a higher affinity. Since bicalutamide has partial androgen-receptor agonist activity, disease progression may be observed following a period of its use, particularly in the setting of androgen-receptor overexpression frequently observed in CRPC; this possibly accounts for the inadequate response in our patient. Enzalutamide, unlike bicalutamide, lacks agonist activity for the wild-type androgen receptor and targets several steps in the androgen-receptor signalling pathway.3

The use of enzalutamide in our patient is supported by the results of the randomized phase 2 trials - TERRAIN and STRIVE, which showed significant and clinically meaningful benefits of enzalutamide compared with bicalutamide in improving progression-free survival (PFS), PSA progression, PSA response, objective tumour response, and quality of life in men with metastatic CPRC.3,4

In the TERRAIN trial, the first randomized head-to-head comparison of the efficacy and safety of enzalutamide vs bicalutamide in patients with metastatic CRPC, median PFS in the enzalutamide group was 15.7 months vs 5.8 months in the bicalutamide group (hazard ratio [HR], 0.44; 95 percent confidence interval [CI], 0.34 to 0.57; p<0.0001). The median time to a PSA progression event was 19.4 months for patients in the enzalutamide group vs 5.8 months for those in the bicalutamide group (HR, 0.28; 95 percent CI, 0.20 to 0.39; p<0.0001), with declines in PSA of at least 50 percent noted in 82 percent of patients in the enzalutamide group vs 21 percent of those in the bicalutamide group.3 Similarly, the STRIVE trial found that enzalutamide reduced the risk of disease progression or death by 76 percent compared with bicalutamide (HR, 0.24; 95 percent CI, 0.18 to 0.32; p<0.001) in patients with nonmetastatic or metastatic CRPC. Median PFS was 19.4 months in the enzalutamide arm vs 5.7 months in the bicalutamide arm. Enzalutamide was also associated with an 81 percent reduction in the risk of PSA progression (HR, 0.19; 95 percent CI, 0.14 to 0.26; p<0.001). Median time to PSA progression was not reached with enzalutamide compared with 8.3 months with bicalutamide. As the STRIVE trial included patients with nonmetastatic CRPC, the results suggested that patients treated with enzalutamide either early in their disease or after development of metastases can obtain greater clinical benefit than those treated with bicalutamide.3,4

Our patient tolerated enzalutamide treatment well without experiencing major side effects. The safety profile of enzalutamide in both the TERRAIN and STRIVE trials was favourable and consistent with that in the two large pivotal placebo-controlled phase III trials, PREVAIL (in men with chemotherapy-naive metastatic CRPC) and AFFIRM (in men with progressive disease after chemotherapy), the efficacy and safety results of which formed the basis for approval of enzalutamide for metastatic CRPC. Among the common adverse events reported in enzalutamide trials, fatigue, back pain, hot flashes, falls, hypertension, dizziness, and decreased appetite were reported more frequently with enzalutamide than with bicalutamide. This is consistent with the more effective androgen-receptor signalling inhibition of enzalutamide.3-6

Screening tests to be carried out before initiating treatment with enzalutamide should include kidney and liver function tests and hepatitis B antibody test. As seizures are a reported but rare adverse event associated with the use of enzalutamide, patients, especially those with a predisposition to or a history of seizures, should be advised on the risk of developing seizures while on enzalutamide and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.7

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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.