**1. Introduction**

Prostate cancer is the most frequently diagnosed malignancy in North America and second leading cause of cancer-related death (Jemal *et al.*, 2010). Despite effective local therapy, prostate cancer often recurs. Standard therapy for recurrent or metastatic prostate cancer remains androgen deprivation therapy (ADT) which is highly effective but not durable (Sharifi *et al.*, 2005). All patients will eventually progress to castrate resistant prostate cancer (CRPC) where there are few treatment options and until recently survival was a dismal 12- 18 months (Tannock *et al.*, 1996). In this chapter we will review the current treatment approaches for CRPC, but focus primarily on the newly approved options available in the post-docetaxel setting.

Castrate-resistant prostate cancer (CRPC) is defined as prostate cancer progression despite ADT and may present with either increasing serum prostate-specific antigen (PSA) levels, radiologic progression, and/or the appearance of new metastases (Saad and Hotte, 2010). Over the years, advanced prostate cancer has been referred to as hormoneresistant prostate cancer (HRPC) or androgen-insensitive prostate cancer (AIPC), but the name has changed to CRPC to reflect the fact that intracrine/paracrine androgen production and signaling pathways play an important role in mediating resistance to first line ADT. CRPC presents as a spectrum of diseases ranging from patients with rising PSA alone, without metastases or symptoms to patients with rising PSA, progressive metastatic disease and significant symptoms. In patients who develop CRPC and who are relatively asymptomatic, secondary hormonal treatments may be attempted. To date, no study of secondary hormone treatment has demonstrated survival benefits, but most trials have been small, underpowered and confounded by the use of subsequent treatments. In patients who are progressing on ADT, discontinuation of antiandrogens, introduction of low dose prednisone or ketoconazole to block production of adrenal androgens, can offer transient PSA responses and palliative benefits in 30% to 35% of patients (Storlie *et al.*, 1995; Small *et al.*, 2004; Heng and Chi, 2006).

For CRPC patients with symptoms, rapid PSA progression or visceral disease, docetaxel chemotherapy and prednisone is currently considered standard of care. Docetaxel is a

Current Options and Future Directions in Castrate Resistant Prostate (CRPC) 265

p<0.0001). Secondary endpoints including progression free survival (PFS) (2.8 months vs 1.4 months), response rate (14.4% vs 4.4%; p=0.005), and median time to progression (TTP) by tumor assessment (8.8 months vs. 5.4 months; p<0.0001) also favored cabazitaxel. From a toxicity standpoint febrile neutropenia, neutropenia, leukopenia and diarrhea were more common in the cabazitaxel arm. One major concern with cabazitaxel however was a toxic death rate of 5% compared to only 1.9% for mitoxantrone. As cabazitaxel moves out of the controlled clinical trial setting into general use, early and proactive management of the toxicites will be critical. Cabazitaxel was FDA approved in 2010 for patients progressing on or after docetaxel. In the same year, a second drug, Abiraterone

Over the last decade there has been a paradigm shift in the approach to CRPC, where despite castrate testosterone levels, there appears to be continued androgen receptor expression and signaling, suggesting that the androgen receptor axis is still a rational therapeutic target. In CRPC, androgens are mainly produced by the adrenal glands and by the prostate cancer cells themselves. This occurs by the sequential conversion of cholesterol to dihydrotestosterone and testosterone. This conversion is mediated by the CYP17 enzyme, which when inhibited can block androgen production. Ketoconazole, an antifungal agent, was the first generation CYP17 inhibitor that was tested in prostate cancer, with some benefit, but to date no studies have confirmed a survival benefit. On the other hand, abiraterone acetate (abiraterone), an oral, irreversible and more selective inhibitor of CYP17

In Phase I/II testing of abiraterone, there were no dose limiting toxicities, the main side effects were hypokalemia and lower-limb edema (due to the mineralocorticoid excess from the upstream inhibition of 17 alpha-hydroxylase), and antitumor activity was seen at all dose levels (Ryan *et al.*, 2010). A Phase III double blind, randomized, placebo-controlled trial of abiraterone 1000 mg daily plus prednisone (to avoid the mineralocorticoid related effects) versus prednisone alone, with the primary endpoint of OS was initiated (de Bono *et al.*, 2011). In total, 1,195 post-docetaxel CRPC patients were accrued, and treated until clinical or radiographic disease progression. Of note, biochemical progression alone (rising PSA) was not considered sufficient for discontinuation of the study drug. Interim analysis demonstrated increased median OS in the abiraterone arm, at 14.8 months compared to 10.9 months (HR 0.65, 95% CI 0.54-0.77) for prednisone leading to early termination of the trial. Other key endpoints including PSA response, time to PSA progression and radiographic progression free survival were all significantly improved in the abiraterone arm. Time to skeletal related events (SRE), defined as pathologic fracture, spinal cord compression, or palliative radiation therapy or surgery also favored the abiraterone arm. Mineralocorticoid related adverse events, consisting of hypertension and hypokalemia were more common in the abiraterone arm, but grade 3+ events were infrequent. A second Phase III trial of abiraterone in the pre-docetaxel setting has closed to accrual and results will likely be

Since both abiraterone and cabazitaxel are now approved in the post-docetaxel setting, a key question will be to determine the optimal sequencing of these agents. At this point it

was also approved for use in the post-docetaxel setting.

has shown very encouraging results in the post-docetaxel setting.

**3. Abiraterone** 

available in 2012.

member of the taxane family of drugs which binds to tubulin and causes microtubule stabilization, leading to cell cycle arrest in the G2/M phase and subsequently cell death (Jordan *et al.*, 1993). Docetaxel is adminstered every three weeks intravenously at a dose of 75mg/m2 with oral prednisone 5 mg twice daily. This is based on two pivotal randomized phase III trials, the TAX 327 trial and the SWOG 9916 trial. TAX 327 randomized more than 1000 patients to receive docetaxel plus prednisone (weekly or every 3 weeks) or mitoxantrone plus prednisone (the previous first-line option). The every 3 week docetaxel arm had a median survival of 18.9 months compared with 16.5 months in the mitoxantrone arm. PSA response rates (defined as 50% drop in serum PSA level) were 48% in the docetaxel group and 32% in the mitoxantrone arm (Tannock *et al.*, 2004). In the SWOG 9916 study, 770 patients were randomized to receive either docetaxel plus estramustine and prednisone or mitoxantrone plus prednisone. Again the median overall survival was longer (17.5 months vs. 15.6 months, P=0.02 by the log-rank test) and PSA response rates were higher (50% vs. 27%, P<0.001) with docetaxel compared with mitoxantrone (Petrylak *et al.*, 2004). Given the efficacy of docetaxel as a single agent and potential thromboembolic toxicity from the addition of estramustine, docetaxel alone with daily prednisone became the standard approach. Although in the trial setting, patients received up to 10 cycles of treatment, in routine practice where patients are less fit, an average of 7 cycles is the length of treatment (Chin *et al.*, 2010). Some patients also appear to respond to retreatment with docetaxel, raising the concept of docetaxel refractory vs. docetaxel resistant disease (Chin *et al.*, 2010). Nonetheless, all patients will eventually develop taxane resistance and progress. In the second line setting, mitoxantrone chemotherapy has palliative benefits, but does not offer a survival advantage, underscoring the need for new strategies in the post-docetaxel setting (Tannock *et al.*, 1996).

Much of the research in the post-docetaxel setting has focused on understanding taxane resistance. Several mechanisms have been proposed including alterations in both docetaxel uptake and retention in cells; changes to tubulin affecting binding sites for docetaxel; and changes in the androgen receptor (AR), which may also contribute in part to the anticancer activity of docetaxel (Gan and Kavallaris, 2008; Seruga *et al.*, 2010). Strategies aimed at overcoming taxane resistance may extend the therapeutic benefit of the taxanes in CRPC.
