Maarten van der Doelen

General introduction and outline of the thesis

GENERAL INTRODUCTION Prostate cancer

1

Globally, prostate cancer is the second most frequently diagnosed cancer in men, with an estimated 1.4 million new cases in 2020. (1) Prostate cancer is the fifth cause of cancer-related death in men worldwide. In the Netherlands, prostate cancer is the most commonly diagnosed cancer in men. In 2019, 13,500 patients were diagnosed with prostate cancer and nearly 3,000 men died from prostate cancer. (2, 3) Prostate cancer is usually diagnosed in men above 60 years of age. The majority of patients presents with localized prostate cancer. Depending on the grade and stage of the disease, treatment options for localized prostate cancer include active surveillance, focal and brachytherapy, external beam radiotherapy, and radical prostatectomy. (4) These therapies are often successful, resulting in long-term disease control and increased prostate cancer-specific survival. (5, 6) However, when the disease metastasizes, the prognosis is worse. In case of newly diagnosed metastatic prostate cancer, the median overall survival (OS) is limited to approximately 42 months. (7) In addition, metastatic prostate cancer may cause considerable pain, impaired mobility, bone marrow failure and skeletal-related events, including pathological fractures and spinal cord compression. (8, 9) Treatment of metastatic prostate cancer Androgen deprivation therapy (ADT) with bilateral orchiectomy or luteinizing hormone releasing hormone agonists or antagonists is standard of care for patients with metastatic prostate cancer, based on benefit in terms of quality of life and reduction of disease-associated morbidity. (10, 11) Although most patients initially respond to ADT, the disease eventually progresses to castration-resistant prostate cancer (CRPC), as a result of extragonadal (e.g. commensal intestinal microbiota) and intratumoral androgen synthesis and altered androgen receptor signaling. (12, 13) The transition to CRPC is known to be inevitably lethal, although survival has improved significantly since the approval of several novel life-prolonging agents following positive outcomes of pivotal phase 3 trials. (14) In 2004, docetaxel, a taxane-based chemotherapeutic drug, was the first agent that was shown to prolong survival in metastatic CRPC (mCRPC) patients. (15, 16) In 2010, cabazitaxel chemotherapy was registered for the treatment of men with disease progression after docetaxel chemotherapy. (17) Also in 2010, the autologous immunotherapeutic agent sipuleucel-T was shown to provide survival advantage in

11