Chapter 16: Management of Castration-Resistant Prostate Cancer

Chapter 16

Management of Castration-Resistant Prostate Cancer

Roger S. Kirby1, Prokar Dasgupta2 and John M. Fitzpatrick3

1The Prostate Centre, London, UK

2Department of Urology, King's College London, Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK

3UCD School of Medicine and Medical Science, Mater Misericordiae University Hospital, University College Dublin, Dublin, Ireland

Overview

There is new hope for patients with castrate-resistant prostate cancer
Docetaxel-based chemotherapy can improve survival in some patients
Cabazitaxel is a new generation taxane for docetaxel-resistant patients
Abiraterone has shown promising results in Phase II and III trials
Sipuleucel-T is the first active immunotherapy to demonstrate an improvement in overall survival for advanced prostate cancer

Introduction

The survival of men with castration-resistant prostate cancer (CRPC) has generally been regarded as poor. However, the median survival in recent Phase III studies has ranged from 12.2 to 21.7 months, with improvements in survival seen mostly with docetaxel-based regimens. Two publications, both appearing in 2004, firmly established the benefits of this therapy. In the landmark TAX-327 trial, 1006 chemotherapy-naïve CRPC patients were randomised to three different treatment arms: docetaxel 30 mg/m2 every week, docetaxel 75 mg/m2 every three weeks and mitoxantrone 12 mg/m2 every three weeks. All patients received prednisone 5 mg orally twice a day. Patients receiving docetaxel every three weeks had a significant improvement of survival compared to weekly docetaxel and mitoxantrone (18.9 months vs 16.5 months; p < 0.009). PSA response, pain control and quality of life were also significantly better with docetaxel every three weeks compared to mitoxantrone. An update of the results of TAX-327 trial published in 2007 showed a survival benefit of docetaxel every three weeks compared to mitoxantrone and no survival benefit with the weekly docetaxel. At three years, survival was 17.2% for docetaxel every three weeks compared to 12.8% with mitoxantrone (p = 0.005).

The Southwest Oncology Group (SWOG) 99-16 study also shows survival benefit with docetaxel. Some 674 patients with metastatic CRPC were randomised to docetaxel/estramustine and mitoxantrone/prednisone arms. Treatment regimen was 280 mg of estramustine three times daily on days 1 through 5, docetaxel 60 mg/m2 on day 2 in the docetaxel arm and 12 mg of mitoxantrone mg/m2 on day 1 plus 5 mg of prednisone twice daily in the mitoxantrone arm. Docetaxel was reported to be superior to mitoxantrone with a median survival of 17.5 months vs 15.6 months (p = 0.02), median time to progression (6.3 vs 3.2 months; p < 0.001) and PSA declines of 50% (50% vs 27%; p < 0.001). These two trials showed a 20–24% reduction in mortality in patients with CRPC treated with docetaxel-based chemotherapy.

There is now new hope for patients who relapse following docetaxel-based therapy. Until recently, treatment was only palliative, as no therapy had been shown to produce a survival benefit in this setting. However, a new generation taxane, cabazitaxel, has been developed to overcome docetaxel resistance, and is now available in the USA, and hopefully soon in Europe. Cabazitaxel, similar to docetaxel, is a semi-synthetic microtubule stabiliser extracted from needles of the European yew tree. In pre-clinical studies, cabazitaxel offers the advantage of being active in vitro and in vivo in cell lines and tumour models resistant to docetaxel, and shows a better blood–brain barrier penetration than other taxanes. In tumour models sensitive to docetaxel, its anti-tumour activity is comparable to docetaxel. In a large Phase III trial, 755 patients with metastatic CRPC progressing during or after docetaxel treatment were randomised to receive cabazitaxel (25 mg/m2 every three weeks) plus prednisone/prednisolone (10 mg daily) or mitoxantrone (12 mg/m2 every three weeks) plus prednisone/prednisolone, an active treatment commonly used for palliation at this stage of the disease. Primary end-point was overall survival. Cabazitaxel significantly reduced the risk of death by 30% (HR = 0.70, 95%CI [0.59–0.83]; p < 0.0001) with a median overall survival of 15.1 months versus 12.7 months with mitoxantrone. Progression-free survival, tumour response and PSA response were also significantly improved with cabazitaxel compared to mitoxantrone. In this population with very advanced disease and heavily pre-treated with chemotherapy, the most frequent grade 3/4 adverse events observed with cabazitaxel compared to mitoxantrone were neutropenia (81.7% vs 58%), febrile neutropenia (7.5% vs 1.3%) and diarrhoea (6.2% vs 0.3%). Patients should be carefully monitored for these adverse events, especially at treatment initiation, but if they occur they are readily manageable.

The prospects for further improvements in survival for men with CRPC are even more promising, considering that several molecules targeting angiogenesis (aflibercept), endothelin receptor (atrasentan, zibotentan), steroid receptor coactivator (dasatinib), RANK Ligand (denosumab) and immune response (sipuleucel-T, prost-vac VF) are either in late stage of development (Phase III) or actually launched (sipuleucel-T). These have been the subject of a recent review, however, shortage of space precludes the possibility of discussing all of them here. Sipuleucel as immunotherapy is particularly expensive ($98,000) and is discussed elsewhere in this book (Chapter 18).

Among a number of novel targets being evaluated are several endothelin-receptor antagonists. Endothelins (endothelin-1, endothelin-2, and endothelin-3) are regulators of cell proliferation, vasomotor tone, and angiogenesis. The endothelins bind to two receptors, endothelin-A and endothelin-B, and play a major role in tumour growth, proliferation, apoptosis, angiogenesis, and bone metastasis. Patients with metastatic prostate cancer have elevated levels of plasma endothelin-1 compared with patients with organ-confined cancer. Endothelin-A is thought to promote osteoblastic activity characteristic of bone metastases in prostate cancer.

Atrasentan, predominantly an endothelin-A receptor antagonist, was studied in two Phase III trials. In the first study, 809 patients with CRPC were randomised to atrasentan 10 mg daily vs placebo. The primary endpoints were time-to-progression (TTP) which was determined according to radiographic and clinical measures. Atrasentan did not reduce the risk of disease progression relative to the placebo (hazard ratio, 0.89; p = 0.136). In exploratory analyses, however, bone alkaline phosphatase and PSA levels were significantly lower in the atrasentan arm. Atrasentan generally was tolerated well, and the most common adverse events associated with treatment were headache, rhinitis, and peripheral edema, reflecting the vasodilatory and fluid-retention properties of endothelin-A receptor blockade. In a second Phase III trial, 941 men with PSA-only CRPC were randomised to receive atrasentan 10 mg daily vs placebo.

Although not statistically significant, fewer patients treated with atrasentan experienced disease progression compared with placebo (p = 0.288) and the median survival was longer for the atrasentan group (p = 0.176). Although it did not meet the primary endpoint expectations, atrasentan did have an impact on molecular markers that indicate disease progression. There was improvement in bone alkaline phosphatase (-1.51 IU/L (A) vs +2.2 IU/l (P); p = 0.001) and PSA doubling time was delayed (p = 0.031). An ongoing Phase III study, the Southwest Oncology Group trial (SWOG S0421) is evaluating atrasentan in combination with docetaxel/prednisone as a first-line treatment in metastatic CRPC.

Zibotentan (ZD4054) is a specific endothelin A (ETA) receptor antagonist that unlike atrasentan has no detectable activity at the endothelin B (ETB) receptor. The results of early clinical trials supported a large Phase II trial in men with CRPC. A randomised, double-blind, placebo-controlled, parallel-group, Phase II trial was undertaken in 65 centres in 14 countries across Europe, North America, Australasia and South East Asia. A total of 312 patients with HRPC and bone metastases who were pain free or mildly symptomatic for pain were recruited and randomised to receive once daily zibotentan 10 mg (n = 107), or 15 mg (n = 98), or matching placebo (n = 107). The primary endpoint was time to progression, defined as clinical progression, requirement for opiate analgesia, objective progression of soft-tissue metastases, or death in the absence of progression. PSA progression and change in number or appearance of bone metastases on scintigraphic imaging did not count as progression events. Secondary endpoints included overall survival, PSA progression, and safety.

At the primary analysis, no statistically significant difference in time to progression was observed for zibotentan versus placebo (HR: 10 mg, 0.88 [80% CI 0.71, 1.09]; 15 mg, 0.83 [0.66, 1.03]). However, a promising signal for prolonged overall survival was observed in the zibotentan treatment groups versus placebo, based on 40 deaths (HR: zibotentan 10 mg, 0.38 [80% CI 0.22, 0.64], p = 0.019; zibotentan 15 mg, 0.61 [0.38, 0.99], p = 0.190). At the second analysis, after 118 deaths, the survival benefit was sustained (HR versus placebo: zibotentan 10 mg, 0.55 [80% CI 0.41, 0.73], p = 0.008; zibotentan 15 mg, 0.65 [0.49, 0.86], p = 0.052), while there continued to be no significant difference in time to progression. Median overall survival was 24.5 and 23.5 months in the zibotentan 10 mg and 15 mg treatment groups, respectively, compared with 17.3 months in the placebo group. At the final analysis, a total of 211 (68%) deaths had occurred. There was a promising signal for overall survival (HR versus placebo: zibotentan 10 mg, 0.83 [80% CI 0.67, 1.02], p = 0.254; zibotentan 15 mg, 0.76 [0.61, 0.94], p = 0.103), while there continued to be no significant difference in time to progression. Median overall survival was 24.5 and 23.5 months in the zibotentan 10 mg and 15 mg treatment groups, respectively, compared with 17.3 months in the placebo group. Consistent with the previous analyses, no statistically significant differences were observed in TTP for either zibotentan 15 mg compared with placebo (HR 0.86, 80% CI: 0.72–1.04, p = 0.309) or zibotentan 10 mg compared with placebo (HR 1.06, 80% CI: 0.89–1.27, p = 0.673) at the final analysis. No significant differences were observed in time to PSA progression. Adverse events were in line with the expected pharmacodynamic effects of an ETA receptor antagonist, most commonly headache, peripheral oedema and nasal congestion.

The promising improvement in overall survival with zibotentan seen in the Phase II study supports further investigation in Phase III clinical trials, with overall survival as the primary endpoint. The zibotentan ENdoTHelin A inhibitor USE (ENTHUSE) Phase III clinical trial programme consists of three randomised, double-blind trials, which together will include more than 3000 patients with HRPC across more than 400 centres worldwide.

There is also considerable anticipation, and a good deal of media coverage, concerning the prospects for abiraterone. Several preclinical and clinical studies have shown that despite being ‘hormone refractory’, prostate cancer cells continue to express high androgen receptor expression and thus mediate androgen signalling. Abiraterone acetate is a potent and a highly selective irreversible inhibitor of cytochrome P-17 (17 a hydroxylase and C17,20-lyase), a dual enzyme that blocks adrenal androgen production.

In a study, 58 patients who had progressive, metastatic CRPC and had failed hormonal therapy and up to two cytotoxic regimens, including docetaxel, were treated with abiraterone (1,000 mg once daily) and prednisone (5 mg twice daily). Twenty-five of 56 patients (45%) had a PSA decline ≥ 50%. Median time to PSA progression was 169 days. The majority of abiraterone-related adverse events were grades 1–2 and no grade 4 adverse events were reported. Also noted was a significantly better PSA response in the ketoconazole-naïve post-docetaxel CRPC population. A randomised Phase III pivotal study to confirm these results is ongoing.

Recent evidence has also indicated an important role for vaccine-based immunotherapy in CRPC. Sipuleucel-T (Provenge) consists of autologous peripheral blood mononuclear cells, including antigen presenting cells, that have been activated during a defined culture period with a recombinant fusion protein consisting of prostatic acid phosphatase (PAP), an antigen expressed in prostate cancer tissue, linked to granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune cell activator. The patient's peripheral blood mononuclear cells are obtained via a standard leukapheresis procedure approximately three days prior to the infusion date. The active components are autologous antigen presenting cells and human PAP-GM-CSF fusion protein. During culture, the recombinant antigen can bind to and be processed by antigen presenting cells into smaller protein fragments. The recombinant antigen is designed to target antigen presenting cells, and may help direct the immune response to PAP. Minimal residual levels of the intact human PAP-GM-CSF fusion protein are detectable in the final sipuleucel-T product. The cellular composition of sipuleucel-T is dependent on the composition of cells obtained from the patient's leukapheresis. The activated, antigen-loaded APCs are then infused into the patient, where it can potentially stimulate a T cell response against prostate cancer cells. The process is performed three times over the course of a four-week period. The vaccine has been studied in three Phase III clinical trials. In the first Phase III study, D9901, consisting of 127 men with asymptomatic, metastatic CRPC, sipuleucel-T every two weeks for three cycles was compared with placebo in a 2:1 ratio. The final three-year follow-up of the D9901 phase III study showed a median survival benefit of 4.5 months and a threefold improvement in survival at 36 months for patients who were randomised to receive Provenge. In another similar phase III trial, D9902A, 98 men with asymptomatic, metastatic CRPC demonstrated a 21.4% improvement in overall survival (OS) for patients randomised to sipuleucel-T. In both studies, the vaccine was well tolerated, and the most common adverse events were chills and fatigue. The third Phase III trial, D9902B, also known as the IMPACT trial (Immunotherapy for Prostate Adenocarcinoma Treatment) was a randomised, double-blind, placebo-controlled study comparing Provenge with placebo in 512 men with CRPC randomised in 2:1 ratio. The median overall survival favoured the vaccine arm with a 4.1-month increase in overall survival for patients treated with sipuleucel-T (25.8 vs 21.7 months; p = 0.032). Also, the 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group. Therapy with sipuleucel-T was also associated with a positive overall survival effect in an analysis that included 18 additional deaths observed between the data-cutoff and study-completion dates, with a median of 36.5 months of follow-up (hazard ratio, 0.76; 95% CI, 0.61 to 0.95;p = 0.02). Sipuleucel-T is the first active immunotherapy to demonstrate an improvement in overall survival for advanced prostate cancer. Given the short duration of the therapy (one month) and its favourable benefit-to-risk ratio, sipuleucel-T provides an attractive new option for the management of advanced prostate cancer.

Conclusion

In conclusion, a number of promising avenues are now available for men with CRPC. For the present, chemotherapy with docetaxel provides the mainstay, but newer options, including abiratarone, seem promising and are likely to be added to the armamentarium shortly.