Prostate Cancer Chemotherapy in the Era of Targeted Therapy

Home , Cyclophosphamide, Ixabepilone, Satraplatin, Thalidomide

Prostate cancer chemotherapy in the era of targeted therapy

A Michael1, K Syrigos2 and H Pandha1 1Oncology Department, Postgraduate Medical School, University of Surrey, Surrey, UK and 2Oncology Unit, Third Department of Medicine, Sotiria General Hospital, Athens University School of Medicine, Athens, Greece

Prostate cancer is the most common cancer in men accounting for around 24% of all male cancers in United Kingdom. The role of chemotherapy in the neoadjuvant and adjuvant setting is still unclear despite considerable progress in this area. Chemotherapy for advanced prostate cancer has become the standard of care, however options of treatment following taxotere failure are still limited. This review summarizes recent advances in chemotherapy treatment options for early as well as advanced prostate cancer. Prostate Cancer and Prostatic Diseases (2009) 12, 13–16; doi:10.1038/pcan.2008.32; published online 3 June 2008

Keywords: chemotherapy; PSA; targeted therapy

Introduction Neoadjuvant chemotherapy Prostate cancer remains the most common cancer in men Chemotherapy has been tested in the neoadjuvant accounting for around 24% of all male cancers in United context prior to radical prostatectomy. Such studies are Kingdom. The approach to organ-confined disease is difficult to evaluate in view of relatively favourable gradually changing with the emphasis on avoiding prognostic group of patients targeted, end points used unnecessary treatment ‘active surveillance’ and the prostate-specific antigen (PSA), progression-free survival development of local therapies as alternatives to external (PFS) rather than overall survival (OS) and longevity of beam radiotherapy and radical prostatectomy. The role the studies. Fears of alteration of histological features of chemotherapy in the neoadjuvant and adjuvant setting particularly at resection margins in the post-resection to accompany any of these options is still unclear despite tumour have so far been unfounded. The studies considerable progress in other solid tumours in the same invariably extrapolate the treatment approach from context. The optimism for progress in treating organ- positive findings of metastatic studies. Of the agents confined prostate cancer still has to be tempered by the evaluated, taxotere was well tolerated and resulted in lack of effective options for individuals with hormone 81% of patients (with a median follow-up of 26.5 months) refractory prostate cancer (HRPC). In the past few years showing no recurrence in PSA post-prostatectomy.3 taxotere chemotherapy has become a standard of care for Estramustine alone, as well as in combination with HRPC following the landmark TAX 327 and SWOG 9916 taxotere may also be active in this setting with 71–84% of studies that showed that chemotherapy can offer a patients achieving a biochemical disease-free survival of survival advantage and control cancer-related symp- 9–23 months.4–6 A large randomized phase III study of toms.1,2 Beyond taxotere, the patient pathway is very radical prostatectomy alone versus taxotere and andro- uncertain as no current second-line chemotherapeutic gen deprivation before radical prostatectomy (Cancer agent alters the natural history of the disease. There is, and Leukemia Group B—CALGB 90203) for high-risk therefore, a considerable unmet need for a large patient patients is currently ongoing (www.calgb.org/). population worldwide, and this is being actively addressed by the development of studies with novel chemotherapies increasingly in combination with targeted therapies. Adjuvant chemotherapy Adjuvant chemotherapy is the standard of care after radical surgery in most common epithelial cancers such as breast, bowel, lung and ovarian cancer, where it offers a survival advantage but is still associated with acceptable toxicity. The difference in the prostate cancer Correspondence: Dr A Michael, Department of Oncology, context has been the lack of efficacy of a large number of Postgraduate Medical School, University of Surrey, Daphne Jackson chemotherapies in the metastatic setting, unlike in breast Road, Manor Park, Guildford, Surrey GU2 7WG, UK. E-mail: [email protected] and gastrointestinal cancers. At the same time, patients Received 10 April 2008; accepted 5 May 2008; published online 3 June at ‘high risk’ with presumed micrometastatic disease 2008 may be easily identified and targeted for new studies. Prostate cancer chemotherapy A Michael et al

14 Previously, the National Prostate Cancer Project com- tine showed a 48% objective radiological response in the pared cyclophosphamide or estramustine with observa- combination arm versus 32% with ixabepilone alone.15 tion after radical prostatectomy or radiotherapy and The PSA response was 69 versus 48% and time to PSA found that the estramustine-treated group had a signi- progression was 5.2 versus 4.4 months, respectively. ficantly longer PFS than the other groups.7 Adjuvant Ixabepilone following taxotere treatment failure was weekly taxotere in patients with high-risk prostate cancer compared to mitoxantrone.16 A PSA response was seen after radical prostatectomy8 has been reported recently. in 20% of patients treated with mitoxantrone versus 17% At a median follow-up of 28 months (range 10.5–38.5), on the ixabepilone arm; the MS was 13 and 12 months, the median PFS of 15.7 months was longer than the respectively. Epothilone B (patupilone) is also active in predicted 10-month median PFS for a matched popu- patients who had previous taxane therapy and asso- lation. Two large randomized phase III studies are ciated with a 25% PSA response.17 currently under way: the SWOG 9921 trial compares Several novel-targeted agents have now been used in mitoxantrone/prednisolone in addition to 2 years of HRPC in combination with chemotherapy or as single hormone treatment versus hormone treatment alone agents. One of the most active drugs is atrasentan, an (www.swog.org). The TAX 3501 study compares taxotere endothelin-A receptor antagonist. Endothelin-1 pro- in a four-arm study with immediate versus delayed motes tumour growth and progression and may be hormone deprivation therapy. involved in the development of bone metastases.18 Atrasentan has been subjected to a number of studies: a meta-analysis of the data showed a significantly longer Chemotherapy for metastatic disease time to disease progression, longer time to bone pain and longer time to biochemical progression.19 The eventual Despite the advent of molecular-based therapy and anti- utility of atresentan may be in combination with other angiogenic strategies, there has been intense activity in agents such as docetaxel or other chemotherapy agents. evaluating new chemotherapeutic agents in the meta- Angiogenesis inhibitors such as bevacizumab have static setting. Satraplatin is a third generation platinum been tested in HRPC in combination with taxotere and compound, structurally similar to cisplatin and orally estramustine. The CALGB 90006 trial showed very high bioavailable.9 Phase II data showed promising results responses with 81% of patients achieving a PSA with median survival (MS) of 16.7 months, and median response, as compared to 68% in patients treated with PFS of 7.7 months.10 On the basis of the results of this taxotere and estramustine alone.20 In this study, the trial, a large phase III trial was organized by European overall MS was 21 versus 19 months, respectively. A Organisation for Research and Treatment of Cancer. large phase III study CALGB 90401 of taxotere and Unfortunately, due to the problems with the sponsoring prednisolone with and without bevacizumab is currently company the trial recruitment was terminated after only ongoing. 50 out of 380 patients were enrolled.11 The analysis of Thalidomide as an anti-angiogenic and immuno- the 50 patients showed the median PFS twice as long on stimulatory agent has undergone phase II evaluation the satraplatin arm (5.2 versus 2.6 months) and there was in prostate cancer as a single agent. A combination a trend towards improved OS, 14.9 versus 11.9 months. of thalidomide and taxotere resulted in 53% PSA Two further satraplatin studies were terminated early response and increased median time to disease progres- (CA142-029 and CA142-026) and there is no data analysis sion of 5.9 months.21 The addition of bevacizumab to this available. Satraplatin in second-line chemotherapy set- combination resulted in not only higher responses but ting, after taxotere failure, was investigated in a SPARC also high toxicity.22 A PSA response was reported in 87% (SatraPlatin Against Refractory Cancers) trial. The multi- of patients but 12.8% had febrile neutropenia and several centre phase III study was reported in 2007.12 A total of patients had significant toxicities such as syncope, grade 950 patients were accrued. Patients in the satraplatin arm 3 bleeding, colon perforation or fistula formation and had a 31% reduction in the risk of PFS events compared thrombosis. to placebo (HR: 0.69; confidence interval, CI: 0.5–0.8), Gefitinib, an orally active epidermal growth factor objective tumour response (7 versus 1%) and pain receptor tyrosine kinase inhibitor is reported to be response (24 versus 14%). The commonest side effect moderately active in HRPC as a single agent, however was myelosupression, although grade 4 toxicity was the comparison with placebo showed no difference in uncommon (4%). Unfortunately, the trial did not achieve time to progression, progression rate or OS.23 In combina- the end point of OS. The MS was 61.3 weeks for the tion with prednisolone it appears to achieve PSA control satraplatin arm compared to 61.4 weeks for the control and prolongs patients survival.24 A total of 82 patients group and the hazard ratio was 0.97 (95% CI: 0.83, 1.13). were enrolled and median time to death was 26.5 months A novel class of tubule-polymerising agents, epothi- as compared to 20.5 months in placebo group. lones, has been tested in metastatic HRPC. The drugs act Vitamin D analogues show anti-tumour activity in by stabilising cellular microtubules inducing mitotic several prostate cancer models.25 The mode of action arrest, in a similar way to taxanes. They have been is by inhibition of proliferation and cell-cycle arrest, shown to be effective in taxane-sensitive and taxane- induction of apoptosis and reduction of invasiveness and resistant tumour cell lines.13 Epothilones were tested as angiogenesis.26–28 Phase II on data on 26 patients of first-line treatment for HRPC as well as second-line combination of DN-101 with taxotere in patients with chemotherapy. A phase II study of ixabepilone, by South- HRPC previously treated with taxotere showed that it is West Oncology Group showed median PFS of 6 months, a well-tolerated and active combination.29 A randomized MS of 18 months and 39% of patients had a true (X50%, phase III study of high-dose calcitriol plus taxotere sustained over two readings 4 weeks apart) PSA versus placebo plus taxotere (ASCENT study) confirmed response.14 Ixabepilone in combination with estramus- the above results.30 Overall PSA response rates were 63%

Prostate Cancer and Prostatic Diseases Prostate cancer chemotherapy A Michael et al 15 (DN-101) and 52% (placebo). Grade 3/4 adverse events 8 Kibel AS, Rosenbaum E, Kattan MW, Picus J, Dreicer R, Klein EA were frequent—58%, but the placebo group recorded et al. Adjuvant weekly docetaxel for patients with high risk 70% rate. The analysis showed a trend towards improve- prostate cancer after radical prostatectomy: a multi-institutional ment in survival but survival was not a primary end pilot study. JUrol2007; 177: 1777–1781. point. The ASCENT II study comparing survival with 9 Wosikowski K, Lamphere L, Unteregger G, Jung V, Kaplan F, weekly or every 3 weeks doses of docetaxel in combina- Xu JP et al. Preclinical antitumor activity of the oral platinum analog satraplatin. Cancer Chemother Pharmacol 2007; 60: 589–600. tion with DN-101 with standard docetaxel and predni- 10 Latif T, Wood L, Connell C, Smith DC, Vaughn D, Lebwohl D sone was closed due to safety issues and imbalance of et al. Phase II study of oral bis (aceto) ammine dichloro deaths between the two treatment arms. (cyclohexamine) platinum (IV) (JM-216, BMS-182751) given Other new drugs that are currently in early phase daily Â 5 in hormone refractory prostate cancer (HRPC). Invest trials for HRPC include Halichondron B Analog-E7389, New Drugs 2005; 23: 79–84. an antimicrotubule agent, and Ispinesib (SB-715992) 11 Sternberg CN, Whelan P, Hetherington J, Paluchowska B, acting on mitotic protein subsequently leading to cell- Slee PH, Vekemans K et al. Phase III trial of satraplatin, an oral cycle arrest and cell death. platinum plus prednisone vs prednisone alone in patients with Various chemotherapy combinations have been tried hormone-refractory prostate cancer. Oncology 2005; 68: 2–9. as a second-line treatment but none of the options have 12 Petrylak DP, Sartor O, Witjes F, Ferrero J, Berry WR, Koletsky A had any impact on OS. Vinorelbine and estramustine et al. A phase III, randomized, double-blind trial of satraplatin and prednisone vs placebo and prednisone for patients with demonstrated activity and longer median OS, the 31 hormone refractory prostate cancer (HRPC). Prostate Cancer numbers of patients treated however were very small. Symp 2007; Abstract 145. Taxotere in combintaion with carboplatin is also active 13 Lee FY, Borzilleri R, Fairchild CR, Kim SH, Long BH, Reventos- 32 with PSA responses seen in 18% of patients. Suarez C et al. BMS-247550: a novel epothilone analog with a Chemotherapy with taxotere is now a standard mode of action similar to paclitaxel but possessing superior approach for HRPC. However, significant numbers antitumor efficacy. 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