Trial PROSPERs China’s fight against advancing prostate cancer

It might be coincidental. But eight months after a joint study by the Peking First University Hospital and National Urological Cancer Center of China in Beijing found a lack of effective therapies in the world’s most populous country for patients with advanced prostate cancer, China’s medicine regulator, the National Medical Products Administration (NMPA), approved the oral androgen-receptor inhibitor enzalutamide for the treatment of adult men with non-metastatic castration-resistant prostate cancer (nmCRPC) with high risk of metastasis.

This was the second approved indication in China for enzalutamide, which was already available for adult men with metastatic castration-resistant prostate cancer (mCRPC) who have been diagnosed as either being asymptomatic or mildly symptomatic after failure of androgen deprivation therapy (ADT), and in whom chemotherapy was not yet indicated.

The approval was based on results from the Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer (PROSPER) trial, a double-blind, placebo-controlled, pivotal Phase III trial that evaluated enzalutamide plus ADT versus placebo plus ADT in 1,401 men with nmCRPC and rapidly rising prostate-specific antigen (PSA) levels.

According to a recent paper published in the Chinese Journal of Cancer Research (CJCR), prostate cancer was the most common tumour in male urology-related cancers in China (‘Chinese guidelines for diagnosis and treatment of prostate cancer 2018’; Chin J Cancer Res. 2019 Feb; 31(1): 67–83; doi: 10.21147/j.issn.1000-9604.2019.01.04).

Prevalence
Citing data from the China National Cancer Registration Institute, the paper stated that, since 2008, prostate cancer has become the country’s most common tumour in male urinary malignancies.

The incidence rate in the country, authors said, was 9.80/100,000 in 2014 and ranked as the sixth most-common malignancy in male malignant tumours; while the prostate cancer mortality rate was 4.22/100,000, and the disease was the ninth common cause of death in all male malignancies.

Emphasising that the incidence of prostate cancer in China varied widely between urban and rural areas, with especially high incidence in large cities, they said that the prevalence in 2014 in urban and rural areas was 13.57/100,000 and 5.35/100,000, respectively.

“With population over 65 years old accounting for more than 10 per cent of the total population in Shanghai, it could be expected that the incidence of prostate cancer would increase dramatically,” they noted.

“In China, only 30 per cent of newly diagnosed patients are clinically localised, and the rest are locally advanced or extensively metastatic disease, who have lost the chance of radical treatment with poor prognosis.”

New treatments
Dr Andrew Krivoshik, Senior Vice President and Global Therapeutic Area Head, Oncology Development, at enzalutamide manufacturer, Astellas, said that in order to maintain quality of life for men with non-metastatic prostate cancer, new treatments to delay the progression of prostate cancer and prevent it from spreading to other areas in the body were required.

“In clinical studies, enzalutamide significantly reduced the risk of the cancer spreading or death compared to placebo alone,” Dr Krivoshik said.

PROSPER met its primary endpoint of metastasis-free survival (MFS), with a median MFS of 36.6 months for men who received enzalutamide plus ADT, compared to 14.7 months with placebo plus ADT.

The multinational trial enrolled suitable patients with nmCRPC at sites in the United States (US), Canada, Europe, South America, and the Asia-Pacific region.
Participants had been diagnosed with prostate cancer that had progressed, based on a rising PSA level despite ADT, but who had no symptoms and no prior or present evidence of metastatic disease.

The trial evaluated enzalutamide at a dose of 160 mg taken orally once daily plus ADT, versus placebo plus ADT.

Trial results
Results demonstrated a 71 per cent reduction in the risk of radiographic progression or death in men who received enzalutamide plus ADT, compared to placebo plus ADT.

The most common adverse events of any grade for patients ≥10 per cent and higher for enzalutamide plus ADT versus placebo plus ADT were fatigue (33% vs 14%), hot flush (13% vs 8%), hypertension (12% vs 5%), nausea (11% vs 9%), fall (11% vs 4%), dizziness (10% vs 4%) and decreased appetite (10% vs 4%).

These results were published in the New England Journal of Medicine (NEJM) in 2018.

Results from the study’s overall survival (OS) secondary endpoint were published in the NEJM earlier last year (‘Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer’, N Engl J Med 2020; 382:2197-2206; doi: 10.1056/NEJMoa2003892).

Writing in June’s NEJM, Sternberg et al stated that it was estimated that bone metastases developed in one-third of nmCRPC patients within two years of diagnosis.

Delaying the length of time it took for metastasis to develop, they said, was “a clinically relevant goal” because mCRPC was associated with decreased OS, worsening quality of life, and increased healthcare-related costs.

Enzalutamide, they said, was associated with a better health-related quality of life and with a significantly lower risk of PSA progression, as well as with a longer time to use of subsequent antineoplastic therapy than ADT alone.

“Although delaying metastasis and maintaining quality of life are meaningful outcomes, overall survival has long been considered an important endpoint and the standard for regulatory approval,” they wrote.

Commentary
Commenting on their research, the team said, that in line with recent studies, their results added to the growing body of evidence that androgen-receptor inhibitors not only delayed the time to metastasis, but also improved OS among men with nmCRPC.

“Enzalutamide prolongs survival in both non-metastatic and metastatic castration-resistant prostate cancer.

“In our trial, enzalutamide treatment in men with nmCRPC and rapidly increasing PSA levels resulted in a significantly longer overall survival than placebo,” they added, noting that the adverse event profile was similar to the established safety profile of enzalutamide.

Three months earlier, a study in the Journal of Cancer reported that prostate cancer was often diagnosed at a locally advanced or metastatic stage in China, resulting in a high mortality-to-incidence ratio which was close to 50 per cent, (‘Early Diagnosis of Prostate Cancer from the Perspective of Chinese Physicians’, J Cancer 2020; 11(11):3264-3273; doi:10.7150/jca.36697).

Early diagnosis was essential for reducing rates of prostate cancer mortality in China, due to a lack of effective treatments for advanced disease in the country, Yu and Zhou noted.

Previously, in the CJCR, Chen et al said common cancer types in urban areas in China were more similar to those in developed regions in the world, where the incidences of cancers relating to obesity and westernised lifestyles were high, including colorectal cancer, prostate cancer, kidney cancer and bladder cancer (‘Cancer incidence and mortality in China, 2014’; Chin J Cancer Res. 2018 Feb; 30(1): 1–12; doi: 10.21147/j.issn.1000-9604.2018.01.01).

They also observed that a heavy cancer burden and its disparities between area, sex and age group posed a major challenge to public health authorities in China.
Commenting on China’s medicine regulator’s decision to grant approval for enzalutamide, Astellas’ Greater China Commercial President, Hiroshi Hamaguchi, said the company was looking forward to assisting more patients and clinicians across the country, with more than 1.44 billion citizens in 2019.

“Enzalutamide in non-metastatic castration-resistant prostate cancer provides patients and their doctors with an important new option for the treatment of their advancing prostate cancer,” he added.