Rapid bench to bed in management of metastatic prostate cancer.

Prostate cancer exemplifies heterogeneity among human cancers, is the most frequently diagnosed noncutaneous cancer in western countries and the incidence rising in countries such as India.[12] Whereas most men with prostate cancer are diagnosed with apparently localized and often indolent disease, a vast majority of men dying from prostate cancer either present with metastatic disease or high risks disease such as Gleason grade >7 or non-organ confined disease.[3] Although metastatic prostate cancer (mPC) is incurable, the disease often can have a prolonged course, and thereby necessitate management strategies of a chronic disease. Men with mPC have a median survival of about 5 years.[3] Androgen deprivation therapy (ADT) has been the mainstay of treatment for men diagnosed or suspected to have mPC for decades. While ADT has proven benefit in symptomatic improvement in men with mPC, the evidence supporting improvement in survival with primary ADT alone for localized or mPC is less than convincing. Prolonged ADT is fraught with significant and severe side effects including but not limited to hot flashes, decreased energy and libido, erectile dysfunction, anemia, bone fractures, osteoporosis, increased risks of cardiac events, cognitive difficulties, and most importantly inevitable progression to castration resistance in about 3 years.[4]

The famine of options for men with mPC ended at the turn of the 21st century and is replaced with a glut of treatment options in the management of men with advanced prostate cancer.[5] While prior chemotherapeutic agents such as mitoxantrone produced symptomatic improvement in mPC, docetaxel became the first chemotherapeutic agent to show improved survival in men with castration-resistant prostate cancer (CRPC) by two large randomized contemporaneously performed independent Phase III clinical trials.[67] However, resistance to docetaxel and progression of disease eventually ensues creating a postchemotherapy space. An improvement in survival was demonstrated by another large Phase III randomized in men progressing on docetaxel chemotherapy using second-line chemotherapy with cabazitaxel belonging to the same family of taxanes but with distinct mechanisms of actions.[8] Studies are underway evaluating cabazitaxel as first-line chemotherapy in mPC.[9] Moreover, three large Phase III studies using docetaxel concurrently with ADT were done in men with androgen-sensitive mPC, of which 2 studies showed dramatic improvement in survival of over a year in men receiving docetaxel with ADT compared to ADT alone in men with large volume disease.[10]

The lack of efficacy of ADT alone in unequivocally improving survival in men mPC was not properly understood until basic research demonstrated that while serum testosterone remains low in men on ADT, sufficient levels of androgens were available in prostate cancer tissue driving disease progression. Rapid efforts to combat tissue androgens led to the development and initial approval of abiraterone, a Cyp17A inhibitor that decreases androgen synthesis, and enzalutamide, a second-generation androgen receptor antagonist in postchemotherapy space. Furthermore, abiraterone and enzalutamide also showed improvement in survival in men who have not undergone chemotherapy and therefore commonly used as first-line therapy in men progressing to castration resistance.[11121314]

Sipuleucel-T was the first cancer vaccine approved for use in humans based on improvement in overall survival in men with CRPC demonstrated by 2 large Phase II and a Phase III clinical trial in patients with minimally symptomatic disease.[15] Radium-223, an alpha-emitting radioisotope was approved for treatment of men with CRPC and symptomatic bone metastasis following demonstrable improvement in overall survival in a large Phase III trial.[16] Unlike second-generation antiandrogens that were independently studied in pre- and post-chemotherapy spaces, Sipuleucel-T and Radium-223 were studied in patients with or without prior Docetaxel chemotherapy.

A total of 6 novel therapeutic agents were approved within a decade for men with metastatic CRPC, which lead to additional questions regarding the sequencing of medications. The effectiveness of docetaxel with concurrent ADT in improving overall survival in men with large volume hormone naïve mPC has resulted in the combination being used as first line therapy. Men progressing following the combination treatment or CRPC in men with low volume disease treated by ADT alone could be offered one or combination of several remaining options. A large Phase II study comparing enzalutamide to bicalutamide in with initial progression to CRPC demonstrated significant improvement in progression-free survival in men treated with enzalutamide suggesting that enzautamide may be the preferred drug in this setting.[1718] However, head to head comparative study between enzalutamide and abiraterone had not been done, which makes the choice between the two drugs on initial progression to CRPC somewhat empirical. The cross-resistance between second-generation antiandrogens abiraterone and enzalutamide is apparent.[19] The choice of agents is likely to depend on patient symptoms, need for prescribing steroids with abiraterone, side effect profile, costs, and availability.

While improvement in survival of over a year has been demonstrated in men with large volume hormone naïve mPC has been demonstrated with upfront docetaxel and concurrent ADT, a common theme among all studies done in men with CRPC is an improvement in overall survival ranging 2–4 months. Whether sequencing of medications will provide cumulative survival benefit remains to be answered. The heterogeneity in human cancers and prostate cancer, in particular, pose a fundamental challenge of effective targeting of all clones simultaneously with acceptable toxicities. Combinatorial, sequencing, and varying dosing strategies are being explored in use of the novel agents in mPC, which will provide additional insights for utilization of the medications.[20] While androgen signaling is well studied and successfully targeted to date, emerging data suggest a future major role for nonandrogen signaling pathways in prostate cancer that could lead to additional diagnostic and therapeutic strategies.[21]