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Pomalidomide plus low-dose dexa-methasone has now advanced into clini-cal trials in combination with a variety of other agents in patients with RRMM. A phase III study to compare the efficacy of pomalidomide, bortezomib and low-dose dexamethasone versus bortezomib and low-dose dexamethasone in individu-als with RRMM (OPTIMISMM) is now recruiting patients.8 As renal insufficiency is a common problem in patients with mul-tiple myeloma, a phase I dose-escalation study to determine the pharma cokinetics and safety of pomalidomide when given in combi nation with low-dose dexamethasone in patients with impaired renal function is also being performed.9

The incorporation of immunomodu-latory drugs, such as thalidomide and lenalidomide, and the proteasome inhibi-tor bortezomib into the treatment of multi ple myeloma during the past decade represented a leap forward in the therapeu-tic para digm for this disease. Pomalidomide and c arfilzomib—a next-generation pro-teasome inhibitor recently approved in the USA—have resulted in incremental and modest advances in PFS and overall sur-vival, providing further steps in the right direction. However, we are ready for the next leap. Hopefully, this will be provi ded by the develop ment of mono clonal antibodies to antigens overexpressed on plasma cells that are already giving promising results in clinical trials.10

Washington University, School of Medicine, Section of BMT and Leukemia, Campus Box 8007, 660 South Euclid Avenue, Saint Louis, MO 63110, USA. rvij@dom.wustl.edu

Competing interestsThe author declares associations with the following companies: Bristol-Myers Squibb, Celgene Corporation, Eli Lilly, Millennium Pharmaceuticals, Onyx Pharmaceuticals. See the article online for full details of the relationships.

1. Kumar, S. K. et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia 26, 149–157 (2012).

2. Siegel, D. S. et al. Long-term safety and efficacy of pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in relapsed and refractory multiple myeloma (RRMM) patients enrolled in the MM-002 phase II trial [abstract]. J. Clin. Oncol. 31 (Suppl.), a8588 (2013).

3. San Miguel, J. et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. http://dx.doi.org/10.1016/S1470-2045(13)70380-2.

4. Schey, S. A. et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J. Clin. Oncol. 22, 3269–3276 (2004).

5. Lacy, M. Q. et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J. Clin. Oncol. 27, 5008–5014 (2009).

6. Richardson, P. G. et al. Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood 121, 1961–1967 (2013).

7. Leleu, X. et al. Pomalidomide plus low-dose dexamethasone is active and well tolerated in

bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myélome 2009-02. Blood 121, 1968–1975 (2013).

8. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01734928?term=OPTIMISMM&rank=1 (2013).

9. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01575925?term=POMALIDOMIDE+RENAL+INSUFFICIENCY&rank=1 (2013).

10. Lonial, S. et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J. Clin. Oncol. 30, 1953–1959 (2012).

UROLOGICAL CANCER

α-Emitting radium-223—additional choices, more unknownsCelestia Higano

Radium-223 dichloride was recently approved for the treatment of men with symptomatic castration-resistant prostate cancer without visceral disease. An understanding of when to use this first-in-class α-emitting agent in the context of the other new treatments is evolving.Higano, C. Nat. Rev. Clin. Oncol. 10, 612–613 (2013); published online 10 September 2013; doi:10.1038/nrclinonc.2013.168

Radium-223 dichloride (radium-223) is a calcium mimetic that selectively binds to areas of increased bone turnover, such as prostate cancer bone metastases, and emits high-energy α-particles. The agent causes double-strand DNA breaks over a short range (path length <100 μm, equivalent to 2–10 cell diameters), which limits its myelo-toxicity.1,2 Radium-223 is excreted predomi-nantly in the faeces, with only a very small amount excreted in the urine.

Initial evidence supporting the effi-cacy of radium-223 in patients with meta-static castration- resistant prostate cancer (mCRPC) to bone was shown in a placebo-controlled randomized phase  II study (radium-223, n = 33 versus placebo, n = 31)3,4 in which radium-223 prolonged overall sur-vival and the time to first skeletal-related event. These findings led to the design of the phase III Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial, which randomly assigned 921 symptomatic men with mCRPC to bone who had previ-ously received docetaxel, or were not eligible

for or declined docetaxel, to treatment with six injections of radium-223 (50 kBq/kg per month, n = 614) or matching placebo (n = 307).5 All patients also received the best standard care m easures, which could include external-beam radiotherapy, glucocorticoids, antiandrogens, keto conazole, oestrogens or estramustine. However, chemotherapy was not permitted.

The ALSYMPCA investigators recently reported their results, f inding that radium-223 significantly improved overall survival compared with placebo (median 14.9  months versus 11.3  months) and reduced the risk of death by 30% (hazard ratio [HR] 0.70; 95% CI 0.58–0.83; P <0.001).5 Importantly, radium-223 also prolonged time to first symptomatic skeletal event com-pared with placebo (median 15.6 months versus 9.8 months; HR 0.66; 95% CI 0.52–0.83; P <0.001), and was associ ated with a low incidence of haematological adverse events (thrombocytopenia, 12% versus 6%; neutropenia, 5% versus 1%). On the basis of these findings, the FDA approved radium-223 on 15 May 2013 for use in men with symptomatic mCRPC without evidence of visceral disease.

The challenge now is to understand how radium-223 fits into the rapidly changing treatment paradigm for men with mCRPC. Until 2010, only docetaxel had shown

‘‘One difference between radium-223 and the other agents is that radium-223 does not have a systemic effect…’’

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a survival benefit in this population of patients. Since then, the FDA has approved five additional agents that prolong survival in men with mCRPC: sipuleucel-T (2010),6 cabazitaxel (2010),7 abiraterone (2011 and 2012),8,9 enzalutamide (2011)10 and, now, radium-223 (2013).5

To some extent, the presence or absence of symptoms of metastatic disease (usually bone pain) can be helpful when consider-ing treatment options. Sipuleucel-T is approved only in men with asymptomatic or minimally symptomatic mCRCP, whereas radium-223 is approved for patients with symptoms from bone metastases. In addi-tion, the presence of visceral disease pre-cludes the use of radium-223 because it targets only bone metastases; the National Comprehensive Cancer Network (NCCN) guidelines recom mend against using s ipuleucel-T for men with liver metastases or rapidly progressive disease, although the label indication does not prohibit use in these patients. In general, docetaxel is reserved for patients with rapidly progress-ing or symptomatic mCRPC. Now that radium-223 is available, it would seem a logical alternative to treatment with docetaxel, with much less toxicity. However, the ALSYMPCA trial was conducted before the availability of these other agents, and many patients are now being treated with abiraterone, and even enzalutamide, off label—the pivotal phase III Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer (PREVAIL) study survival results have not yet been reported—prior to chemotherapy. How either docetaxel or radium-223 will perform in this new setting is unclear.

One difference between radium-223 and the other agents is that radium-223 does not have a systemic effect; it treats only tumour in bone. As a calcium mimetic that is taken up in areas of new bone formation occurring in and around tumour deposits, radium-223 could have considerable impact on the uptake of technetium-99m on bone-scan imaging. Unfortunately, the effect on bone scans is not known because these were not required in the ALSYMPCA study. Another difference between radium-223 and the other new agents is that the cancer itself is not the direct target. This target difference has potential advantages in that resistance to therapy is unlikely to emerge quickly because radium-223 causes lethal and diffi-cult to repair double-strand DNA breaks rather than interrupting a p roliferation or survival pathway.

The median time to serum prostate- speci f ic ant igen (PSA) increase in the ALSYMPCA trial was 3.6 months in the radium-223 arm versus 3.4 months in the placebo arm (HR 0.64; 95% CI 0.54–0.77; P <0.001).5 Although the hazard ratio and P value were significant, why serum PSA did not decline in most patients in the treatment arm is unclear, especially given the clear benefit in overall survival. Could this be because radium-223 treats only osseous disease and is not expected to have any effect on extraosseous metasta-ses? Indeed, men with positive lymph nodes <3 cm were eligible for ALSYMPCA, and these extra osseous sites could be the source of continued PSA production. The authors did not report the number of patients with extra osseous metastases in the text or supplemen tary information of their publi-cation, and this line of questioning might be worthy of further analysis, if the data are available.

Given the bone-targeting nature of radium-223, combination with other active agents that also treat extra osseous disease is logical. Anecdotally, in some areas of the USA, combinations of radium-223 and abira terone or enzaluta mide are already prescribed, whereas in other areas insurance constraints prohibit such combinations. Future planned trials will formally address such combinations. Outside of a clinical trial, radium-223 should not be combined with chemotherapy owing to the potential for overlapping haematological toxicity; one trial is currently ongoing (NCT01106352).

Over the next few years, we will learn more about how the new drugs fit into the

treatment paradigm for men with mCRPC. Currently, use of radium-223 in the sympto-matic patient who is truly unfit for or refuses docetaxel chemotherapy is clearly a good option. In symptomatic patients who have already received docetaxel, choices for therapy include abiraterone, enzalutamide and cabazitaxel. Assuming many patients will have already received abiraterone, radium-223 has a toxicity profile that is superior to cabazitaxel and is, therefore, an excellent option in patients who relapse after docetaxel.

University of Washington, Seattle Cancer Care Alliance, 825 Eastlake Avenue East, Mailstop G4‑830, Seattle, WA 98109, USA. thigano@u.washington.edu

AcknowledgementsThe author thanks the Department of Defense Prostate Cancer Research Program (USA) for partial support.

Competing interests The author declares an association with the following companies: Bayer, Cougar Biotech, Dendreon, Johnson & Johnson and Sanofi-Aventis. See the article online for full details of the relationships.

1. Henriksen, G., Breistøl, K., Bruland, Ø. S., Fodstad, Ø. & Larsen, R. H. Significant antitumor effect from bone-seeking, α-particle-emitting 223Ra demonstrated in an experimental skeletal metastases model. Cancer Res. 62, 3120–3125 (2002).

2. Henriksen, G., Fisher, D. R., Roeske, J. C., Bruland, Ø. S. & Larsen, R. H. Targeting of osseous sites with α-emitting 223Ra: comparison with the β-emitter 89Sr in mice. J. Nucl. Med. 44, 252–259 (2003).

3. Nilsson, S. et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 8, 587–594 (2007).

4. Nilsson, S. et al. Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases. Clin. Genitourin. Cancer 11, 20–26 (2013).

5. Parker, C. et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N. Engl. J. Med. 369, 213–223 (2013).

6. Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).

7. de Bono, J. S. et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376, 1147–1154 (2010).

8. de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011).

9. Ryan, C. J. et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N. Engl. J. Med. 368, 138–148 (2013).

10. Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012).

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