An Embarrassment of Riches: Approaching Metastatic Castrate Resistant Prostate Cancer Treatment in the Face of New Evidence

Guest post by Tom McFarlane

Introduction

Until relatively recently, metastatic castrate resistant prostate cancer (mCRPC) was a disease with very few treatment options available. Patient options were limited to bisphosphonate use for bony metastases and, eventually, chemotherapy of somewhat questionable efficacy with docetaxel and/or mitoxantrone. Since 2010, there have been several promising agents which have emerged in both the pre-chemo and post-chemo settings in mCRPC which have demonstrated progression-free survival (PFS) and overall survival (OS) benefits. This has clearly been a boon for the patients who suffer from mCPRC, but has raised questions with regard to whether there is an optimal sequence of treatments which would be best administered to this patient group. New guidelines have recently been published by the Canadian Urology Association jointly with the Canadian Urologic Oncology group (CUA-CUOG) in order to try to give some guidance in this new landscape. This article will explore these guidelines and give some perspective on how patients with mCRPC should be managed.

Figure 1. CUA-CUOG guidelines for management of castrate resistant prostate cancer. PSADT: PSA doubling time.

Asymptomatic or mildly symptomatic mCRPC

The management of mCRPC has drastically changed in the last five years given the advent of new treatment options. Whereas once patients of this nature posed a challenge because of a lack of evidence for available interventions, clinicians now have a choice of several efficacious therapies. CUA-CUOG guidelines (Fig. 1) currently suggest the use of abiraterone, an oral androgen biosynthesis inhibitor, in patients with asymptomatic or mildly symptomatic mCRPC as a treatment of choice. This is due in large part to the interim results of the COU-AA-302 trial recently published in the New England Journal of Medicine, where abiraterone plus prednisone increased time to progression to 16.5 months versus 8.3 months seen with prednisone alone (p<0.001), but also because abiraterone currently is the lone agent approved in this specific group of patients by Health Canada. Conversely, the NCCN guidelines for treatment of prostate cancer in the United States also include sipuleucel-T, an immunotherapy, in asymptomatic mCRPC based a 4.1 month improvement in overall survival seen with sipuleucel-T over placebo in the Phase III IMPACT trial (25.8 vs 21.7 months respectively, HR 0.78, p=0.03), and enzalutamide, an androgen receptor antagonist, based on the PREVAIL trial presented earlier this year at the ASCO/ASTRO/SSO Genitourinary Cancers Symposium in San Francisco, where risk of death was reduced by 29% vs. placebo (HR 0.706, p<0.0001) and time to chemotherapy was significantly extended in the patients receiving enzalutamide over placebo (28.0 vs 10.8 months respectively, HR 0.35, p<0.0001).

 

Challenges in the pre-chemotherapy setting

Given the prohibitive cost of sipuleucel-T, which is approximately $93,000 U.S., coupled with its unavailability in Canada, abiraterone and enzalutamide are likely to become the workhorses of treatment in this patient group based on the current data. One of the challenges that clinicians will face is that of deciding which agent to use. There is unlikely to be any direct comparison between the two agents, nor will we likely see any formal data looking at sequencing them. There is, however, a possible mechanistic basis for specific sequencing. Enzalutamide is a strong CYP 3A4 inducer with a relatively long biologic half-life of 5.8 days. Given that abiraterone is a CYP 3A4 substrate, it might be prudent to use abiraterone followed by enzalutamide instead of the reverse sequence if considering using the agents back-to-back. It should be noted, however, that no formal pharmacokinetic study has been done specifically examining this scenario. Further, the question arises as to whether using multiple lines of hormonal therapy despite treatment failures is a viable strategy. This question has yet to be answered fully.

 

Symptomatic mCRPC

Cytotoxic chemotherapy is still considered the treatment of choice in patients who have symptomatic mCRPC, particularly in the setting of visceral metastases. Docetaxel is the drug of choice in these patients as demonstrated in the CUA-CUOG guidelines (Fig 1). Until recently, few useful options existed for patients who failed chemotherapy with docetaxel; however, as in the asymptomatic mCRPC population, clinicians can now choose from several possibilities. Cabazitaxel is a semi-synthetic taxane which was developed to overcome some of the putative resistance mechanisms thought to render prostate cancer cells resistant to docetaxel. The TROPIC trial demonstrated that cabazitaxel has an overall survival benefit when used after docetaxel failure vs. mitoxantrone, which was the previous standard (15.1 vs 12.7 months respectively, HR 0.72, p<0.0001). Similarly, abiraterone and enzalutamide have both shown a survival benefit in this population. In the COU-AA-301 trial, patients with mCRPC who had failed docetaxel derived a significant benefit from abiraterone vs. placebo (14.8 vs 10.9 mos, HR 0.65, p<0.0001). A comparable trial, AFFIRM, was done using enzalutamide vs. placebo (18.4 vs 13.6 mos, HR 0.63, p<0.0001). Another potential option in symptomatic patients is Radium-223 an alpha radiation emitter with a chemical similarity to calcium, particularly in those patients with symptomatic bone metastases. In the ALSYMPCA trial, Radium-223 demonstrated both an improvement in overall survival over placebo (14.2 vs 11.2 mos, HR 0.70, p=0.00185) and an increase in time to next skeletal related event, making it the only agent that has ever shown both these benefits at the same time. It also has the advantage of being very well tolerated with few adverse effects. Radium-223 received Notice of Compliance from Health Canada in March of 2014.

Challenges in the symptomatic mCRPC setting

As in the asymptomatic population, as more therapeutic options become available a major challenge in treating symptomatic patients revolves around sequencing of treatment. Currently we have no available data on using any of the approved treatments for symptomatic mCRPC after prior therapy with abiraterone or enzalutamide. Thus, if these drugs are used prior to chemotherapy in an asymptomatic patient, it is unclear what benefit the various available treatments will have post-chemotherapy.  Investigations are ongoing into the concept of combining androgen biosynthesis inhibitors with androgen receptor blockers, with the idea being that the combination should be synergistic. ARN-509, a Janssen compound similar to enzalutamide, is currently being looked at in combination with abiraterone. Whether this combination would be feasible for funding in a private payer system is somewhat questionable at this point.

In addition, it is not entirely clear what the optimal first line chemotherapy is for symptomatic patients now that there are two options available. The FIRSTANA trial, which is comparing cabazitaxel with docetaxel in chemotherapy-naïve symptomatic mCRPC patients, aims to answer this question, and the final results of this trial are due in January 2015. Finally, with Radium-223 now approved in Canada, consensus is needed on where this therapy should fit into guidelines.

Conclusions

The treatment landscape of prostate cancer is rapidly changing. While in many ways this is a windfall for patients as we have a number of effective treatments we can now offer them, the relative abundance of these creates a dilemma for clinicians. More work is needed to determine the optimal sequencing of these agents so that we can offer the best possible treatment plan to patients who present with mCRPC.

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Tom McFarlane, BScPhm RPh PharmD

  • Clinical Pharmacist, Oncology/Hematology/Palliative Care, Cambridge Memorial Hospital
  • Adjunct Clinical Assistant Professor, School of Pharmacy,  University of Waterloo

References

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2.       NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer V.2 2014. http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed May 27, 2014.

3.       Ryan CJ et al. Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy. N Engl J Med 2013 Jan 10; 368:138-148.

4.       Beer TM et al. Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. N Engl J Med 2014 June 1. DOI: 10.1056/NEJMoa1405095 [e-pub ahead of print]

5.       Kantoff PW et al. Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer. N Engl J Med 2010 Jul 29; 363:411-422.

6.       De Bono JS et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration resistant prostate cancer progressing after docetaxel treatment: a randomized open-label trial. The Lancet 2010; 376(9747):1147-1154.

7.       De Bono JS et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. N Engl J Med 2011 May 26; 364:1995-2005.

8.       Scher HI et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. N Engl J Med 2012 Sep 27; 367:1187-1197.

9.       Parker C et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. N Engl J Med 2013 July 18; 369:213-223.