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Improving the Journey for Men with Metastatic Castrate Resistant Prostate Cancer

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - ECCO-17 - 38th ESMO Multidisciplinary Congress

Amsterdam, The Netherlands / September 27-October 1, 2013

Amsterdam - Prostate cancer (PC) remains the most commonly diagnosed cancer in males and it is the second leading cause of death in men. Skeletal complication is the most important morbidity point in terms of metastases in PC and almost all men with metastatic castration-resistant prostate cancer (mCRPC) will develop metastases to bone. Any reduction in skeletal complications and delay in time to symptomatic events represents a meaningful clinical end point. Until now, none of the bone targeted therapies have been shown to extend survival. According to new evidence, an alpha-emitting radiopharmaceutical not only delays time to symptomatic skeletal events but prolongs overall survival in mCRPC. Together with new castration-specific therapies, this novel approach to treating bone metastases has the potential to extend the journey of men with mCRPC and preserve quality of life along the way.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

“Over 90% of men who die of prostate cancer (PC) will have metastases to the bone,” Dr. Fred Saad, Professor and Chief of Urology, University of Montreal Hospital Centre, told delegates here. Although distinct clinical issues and even prior to the development of metastatic disease, the use of androgen deprivation therapy (ADT) for earlier stage PC often leads to gradual bone loss that surpasses even that of postmenopausal women. “The longer men are exposed to ADT, the greater their risk of osteoporotic fracture”, Dr. Saad added.

Indeed, over a 4 to 5 year follow-up, Shahinian et al. (N Engl J Med 2005; 352:154-64) found that 19.4% of men on ADT had sustained a fracture compared with 12.6% of men who were not on ADT. If a man is started on ADT prior to the appearance of metastatic disease, “they routinely stay on ADT for 10 years before dying of their disease”, Dr. Saad said. Compounding this disease, men who experience a hip fracture have an “even more profound” reduction in survival than women who experience the same fracture.

Equally impactful are vertebral compression fractures, the development of which also amplifies mortality risk over time. “Not all patients who develop prostate cancer require osteoporosis prevention therapy,” Dr. Saad noted. However, those who have a greater than 10% risk of hip fracture based on their WHO Fracture Risk Assessment Tool (FRAX) score, or a greater than 20% risk of other fractures should be considered for treatment. (The FRAX score is available at: https://riskcalculator.fore.org/default.aspx).

Preventing Bone Loss

The bisphosphonates, often used to treat osteoporosis, have long been proven to prevent bone loss associated with the treatment of PC. “The big issue with the oral bisphosphonates is compliance,” Dr. Saad noted. After about 1 year, 70% of men no longer take the prescribed bisphosphonate, largely because of gastrointestinal complaints. Saad et al. (J Natl Cancer Inst 2002; 94:1458-68) were the first to show that zoledronic acid (ZA), a new bisphosphonate at the time, could block bone destruction in men being treated for what was then called hormone-refractory PC and a history of bone metastases. The study demonstrated that compared to placebo, ZA reduced the number of skeletal-related events (SRE) and prolonged the time to first SRE, by approximately 5 months in patients being treated for metastatic PC. 

More recently, Smith et al. (N Engl J Med 2009; 361:745-55) demonstrated that denosumab significantly improved bone mineral density (BMD) in non-metastatic PC patients on ADT over a period of 3 years compared to placebo at every area of BMD tested. Denosumab also reduced new vertebral fractures over the same 3-year study by 65% compared to placebo.  In a direct comparison of ZA to denosumab, Fizazi et al. (Lancet 2011; 377:813-22), found that denosumab reduced the total burden of SREs and prolonged time to first SRE to a greater extent than did ZA in men with bone metastases from castration-resistant prostate cancer (CRPC).

There was however, “no survival difference between ZA and denosumab in this study so I continue to say that we now have 2 active agents to delay or prevent skeletal complications in this setting, denosumab having the advantage over ZA as there is no need to adjust the dose of denosumab for renal function deterioration.” Osteonecrosis of the jaw (ONJ) has emerged as an issue of some concern with long-term treatment with either of these agents—the risk of ONJ being about 1.3% per year of exposure to ZA and about 2% per year with exposure to denosumab.

Risk factors for ONJ include poor oral hygiene and tooth extraction. Improved oral health, in addition to calcium supplements, should help prevent ONJ in patients on bone targeted therapies. “PC is one of the rare metastatic diseases that has hypocalcemia as an issue even before starting any treatment because of the osteoblastic component to it,” Dr. Saad said. “So for any patient who is getting either ZA or denosumab, it is crucially important to make sure patients take calcium [and vitamin D] supplements prior to treatment initiation.” Calcium at a dose of 1000 mg and vitamin D at 1000 units a day should help ensure calcium homeostasis.

Added Survival Advantage

Most recently radium-223, a radionuclide that targets bone metastases, has emerged with an added survival advantage. In the pivotal ALSYMPCA trial (N Engl J Med 2013; 369:213-23) Parker et al. showed that the median time to first symptomatic skeletal event (SSE) was 15.6 months in men with CRPC and symptomatic bone metastases randomized to radium-223 vs 9.8 months for placebo controls (P<0.001). The agent was given at a dose of 50 kBq/kg, with 6 injections given at 4-week intervals.

Overall survival (OS) was also improved by 30% to a median of 14.9 months in the treatment arm compared with 11.3 months for placebo patients (P<0.001). At this year’s meeting, ALSYMPCA investigators reported that the alpha-emitting agent prolonged time to first SSE regardless of current bisphosphonate use; prior docetaxel use, or baseline alkaline phosphatase levels (<220 or ≥220 U/L) (Abstract 2.876). “Bone is the most important morbidity point in terms of the metastatic site in CRPC,” Dr. Joseph O’Sullivan, Professor of Radiation Oncology, Queens University Cancer Centre,  Belfast, Northern Ireland, said in an interview.

“Unlike other drugs, radium-223 improves survival so it’s obviously altering the natural history of the disease. And by regaining some control of disease burden, patients are living longer and it would appear treatment gives them much better pain control as well.” Just how the alpha-emitting agent prolongs OS isn’t clear but one explanation might be related to the drug’s extremely limited radiation radius.

Once it hits the bone (which it does within seconds of being infused), its alpha particles are catastrophically damaging to tumor cells interspersed within bone but not the bone marrow itself. “A tumor cell may become resistant to castration therapy such as abiraterone or enzalutamide but it really can’t become resistant to this agent,” Dr. O’Sullivan observed. “If you can get the drug near the tumor cell, it will kill it.” This mechanism of action probably explains the relatively mild hematological toxicity profile reported here with the radiopharmaceutical, he added (Abstract 2.877). 

Compared to cytotoxic chemotherapy and other radioisotope therapies like beta-emitters, this agent has some effect on neutophils and platelets but grades 3 and 4 hematologic toxicities occurred infrequently in the clinical trial. “In my experience using the drug, the hematologic  toxicity is very manageable,” Dr. O’Sullivan added. In addition, “this is the first BTT that improves quality of life,” Dr. Chris Parker, Royal Marsden NHS Foundation, London, UK added.  Looking at individual quality of life domains in the ALSYMPCA trial, again as reported here (Abstract 2.878), the most profound difference between the radiopharmaceutical and placebo was in pain control.

Significant benefits were also observed within physical, emotional and functional well-being subscales. Over time, quality of life deteriorated in both groups—“no surprise as these men were in the last year or two of their life and quality of life will deteriorate in the end,” Dr. Parker said. “But in the radium-223 arm, quality of life was better preserved for longer than in placebo patients”, which may be more important, as men with mCRPC are often not fit enough to undergo a fairly punishing course of chemotherapy with docetaxel. 

Abiraterone and enzalutamide are already delaying time to chemotherapy. In Dr. O’Sullivan’s opinion, the new alpha-emitting agent will likely do the same, firstly because patients do not have to be all that fit to receive it as it is so well tolerated. And secondly, once a patient has mCRPC, they are going to be symptomatic from metastatic spread to the bone and the ALSYMPCA trial clearly demonstrated that CRPC patients with symptomatic bone disease benefit from this agent.

Summary

In the past few years, a plethora of novel agents has emerged for the treatment of mCRPC and related metastases. The availability of these agents has significantly prolonged the lives of these men to the point where they often live for many years before progressing and dying of their disease. Along the way, virtually all men will develop metastases to the bone and for these men, a novel therapeutic approach can provide significant relief from bone pain, as well as, improve both quality and length of life. 

Note: At press time, radium-223 is not approved in Canada.

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