Preventing Bone Metastases Progression in mCRPC: When is it too late?

Bone metastases in metastatic castration-resistant prostate cancer (mCRPC) can invade a range of sites in the skeleton where they precipitate a spectrum of pathological processes that increase morbidity, negatively affect quality of life, and decrease survival. Not surprisingly, physicians are developing new treatments and treatment paradigms aimed at reducing the incidence of these events.¹

Bone metastases appear most commonly in the ribs, the spine (cervical, thoracic, and lumbar vertebrae, and pelvis), and have also been documented in long bones (femur).²Metastatic growth at these sites gives rise to severe bone pain, often requiring powerful analgesia and external beam radiation treatment. Spinal cord or nerve root compression, myelosuppression, and disturbances in calcium metabolism also commonly occur.^1,3,4

A recent review summarized the pathophysiology of bone pain as, “components of neuropathic, inflammatory and ischemic pain, arising from ectopic sprouting and sensitization of primary afferent sensory nerve fibers within prostate cancer-invaded bones.” It further asserted that metastases arises and is perpetuated by virtue of the cross talk between the osteoclasts and osteoblasts and other factors involved in the bone microenvironment.⁵This multifactorial pathophysiology makes it challenging to manage and an imperative to avoid.¹

A study by Body et al⁶examined data on the management of bone pain in 1305 patients with prostate cancer and bone metastases. They found that ­­­­76% of the patients had been treated with bone-targeting agents for bone pain (34%), high risk of bone complications (33%), number of bone metastases (12%), locations of bone metastases (8%), and prior history of bone complications (6%). Currently. 27% of the patients with bone metastases need powerful opioids for the relief of bone pain.

A recent preclinical study has highlighted a hitherto unreported mechanism that promotes the growth of bone metastases in prostate cancer.⁷Using a mouse model they showed that following injection of prostate cancer cells into the intramedullary cavity of the tibia, tumor growth increased pressure within the mouse tibia. In vitro experiments subsequently revealed that pressure applied to osteocytes facilitated prostate cancer growth and invasion, and this was mediated in part by an upregulation of CLL5 and matrix metalloproteinases in osteocytes. These findings implicate osteocytes, responding to the increased pressure generated by tumor growth, in the orchestration of the metastatic niche within the bone in patients with prostate cancer.⁷This again emphasizes the clinical imperative to reduce the incidence of bone metastases in prostate cancer.

Bone Pain: Impact on Survival and Quality of Life

Several studies have assessed the impact of bone pain on survival and quality of life. In a retrospective analysis, Halabi et al combined data on 599 patients from three randomized controlled trials conducted by the Cancer and Leukemia Group B from 1992 to 1998.⁸The trials recruited patients with progressive CRPC adenocarcinoma of the prostate and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. The Brief Pain Inventory (validated scale) gauged the impact of pain on selected daily activities and QOL. They found a median pain interference score of 17, and a statistically significant association between pain scores and the risk of death. Comparing men with low (<17) and high (&ge;17) pain scores, the median survival times were 17.6 months (95% CI, 16.1-19.1) versus 10.2 months (95% CI, 8.6-11.3), respectively (P<.001). When comparing the same two cohorts, median times to bone progression were 6.7 months (95% CI, 5.8- 7.6) and 3.8 months (95% CI, 3.2-4.3 months), respectively (P<.001). Men with pain scores &ge;17 had a 22% greater risk of bone progression than men with pain scores <17. Median times to PSA progression followed a similar pattern, with 4.0 months (95% CI, 3.0-4.5) versus 2.9 months (95% CI, 2.4-3.5) for scores of <17 and &ge;17 respectively (P<.001).⁸

Using a more recent cohort of patients with mCRPC [Saad 2002], Weinfurt et al sought to investigate the clinical relevance of skeletal-related events (SRE).⁹Health-related quality of life (HRQOL) was measured during the trial using the Functional Assessment of Cancer Therapy-General (FACT-G), the BIP, and the EuroQuol instrument. They used a mixed effects model to estimate outcome changes following a patient&rsquo;s first SRE. Their work showed that SREs have clinically meaningful and significant impact on HRQOL. Physical and emotional well-being declined after pathologic fractures and radiation therapy. Functional well-being dropped after radiation therapy. Significant declines in preference and utility scores were noted after fractures and radiation. Pain intensity only declined after radiation treatment, but not after other SREs.⁹

In another analysis of the same trial, De Puy et al reported the impact of skeletal morbidities on longitudinal patient reported outcomes and survival.^10,11The trial recruited 643 patients, and they received either zoledronic acid or placebo for 15 months. FACT-G and BPI were used to assess outcome measures in patients with and without SREs who survived 6 months post randomization. Patients with no SREs at 6 months (landmark) had significantly greater survival at 360 days post landmark (49.7% vs 28.2%;P= .02). HRQOL measures in the post landmark period, including pain, were worse in patients who experienced SREs during the landmark period. The authors concluded that, &ldquo;Increasing SRE intensity shows a pattern of increasingly decreased survival and poorer HRQOL.&rdquo;¹¹

PSA and Bone Metastases

A major concern for physicians is when to look for bone metastases. This issue has most recently been tackled by a team led by DM Moreira,^12,13who point out that new therapies have been shown to be of benefit to patients with asymptomatic metastatic prostate cancer, and so earlier detection of metastases is essential to improving care.^14-16While metastases can be and are detected by bone scans, there remains the problem of whether or not these scans should be done at preset timing intervals, or should be triggered by clinical or biochemical findings. In a study published in 2014, using the Shared Equal Access Regional Cancer Hospital database, (SEARCH database) Moreira et al showed that PSA levels, PSA doubling time, and PSA velocity were predictors of metastases in patients with increasing PSA levels after radical prostatectomy.¹²

They analyzed data from 401 patients undergoing a bone scan for suspected metastatic disease from 1995 to 2012 at six Veteran Affairs Medical Centers. All patients had bone scans, and their PSA levels and PSA kinetics at the time of scan were available. The secondary objective of the study was to use PSA and PSA doubling time (PSADT) to rank bone scans according to positivity. They found that for patients who were hormone na&iuml;ve, screening for bone metastases should be initiated for a PSADT of <9 months. In contrast, there was only a 2% risk of a positive bone scan if the PSADT was &ge;9 months. This occurred even in men with high PSA values; long PSADT was still associated with a very low risk of a positive scan. In men after androgen deprivation therapy, they could not identify a subgroup where the risk of a positive bone scan was low. Even among patients with very low PSA and PSADT, the risk of a positive bone scan was &ge;10%, and the authors recommended that bone scans should begin early in patients after ADT, even before a PSA level of 5 ng/mL is reached.¹²

In a more recent analysis, again using the SEARCH database, they devised a tool (in the form of a table) to assist physicians in the selection of patients with CRPC who may be in need of bone scans. The table combines PSA and PSADT and stratifies patients according to the risk of having a bone scan. They also point out that the table could be used for the identification of particular populations of patients for specific clinical trials. They found that men with a PSA of <5, 5 to 14.9, 15 to 49.9, and &ge;50 ng/mL had scan positivity of 6%, 14%, 29%, and 57%, respectively (Ptrend <.001). Scan positivity was 11%, 22%, 34%, and 47% for men with PSADT &ge;15, 9 to 14.9, 3 to 8.9, and >3 months, respectively (Ptrend <.001).¹³

Managing Bone Metastases: Bone Targeted Agents

Currently a number of treatments are approved for the management of patients with mCRPC and bone metastases. They include osteoclast-targeting agents, zoledronic acid and denosumab, and radiopharmaceuticals such as &szlig;-particle emitters, strontium-89 chloride and samarium Sm-153 lexidronam, and the &alpha;-particle emitter radium-223.¹

Zoledronic acid and denosumab

A phase III trial of zoledronic acid (a bisphosphonate) versus placebo in 643 patients with mCRPC and bone metastases, without severe bone pain, showed that fewer patients taking zoledronic acid dosed at 4 mg every 3 weeks for 15 months experienced SREs versus placebo (33% vs 44%P= .021); however, survival was not significantly different between the groups. At 24 months of follow-up, zoledronic acid treatment reduced the risk of SREs by 36% versus placebo. Bone pain was also reduced in patients treated with zoledronic acid compared with placebo.^1,10

A phase III trial was conducted on denosumab (a monoclonal antibody against a key activator of osteoclastic resorption, RANKL) versus zoledronic acid.¹⁷The primary endpoint was time to first on-study SRE. Overall survival (OS) and investigator-assessed overall disease progression and PSA levels during the study were among key exploratory endpoints. The study recruited patients with mCRPC and bone metastases who had no prior treatment with bisphosphonates. A total of 1904 patients were randomized, 950 to denosumab and 951 to zoledronic acid. The median time to the first SRE was 20.7 months versus 17.1 months for denosumab and zoledronic acid, respectively (HR 0.82, 95% CI, 0.71-0.95,P= .008). OS and investigator reported disease progression were not significantly different between the groups. Changes in median PSA concentrations and bone pain were also similar between the groups during the study.¹⁷

There are a number of toxicity concerns associated with these agents. Nephrotoxicity is a commonly reported adverse event (AE) for bisphosphonates, necessitating monitoring of serum creatinine and appropriate dose adjustment. Denosumab, however, does not cause nephrotoxicity in men with prostate cancer.¹An integrated analysis of three randomized phase III trials (5723 patients) confirmed that both drugs are associated with hypocalcemia and osteonecrosis of the jaw (ONJ).¹⁸Hypocalcemia incidence was higher among patients treated with denosumab versus zoledronic acid (3.1% vs 1.3% for grade 3/4). ONJ was found to occur more frequently in patients treated with denosumab than zoledronic acid (1.8% vs 1.3%), but the difference is not statistically significant.¹⁸

Radiopharmaceuticals

The status of &szlig;-particle emitters strontium-89 chloride and samarium Sm-153 lexidronam has recently been reviewed by Body et al.¹Considering the evidence, they conclude that although both agents seem to exert clinically relevant analgesic effects in patients with bone pain in mCRPC, they have not been unequivocally shown to reduce the incidence of SREs or to extend survival.¹

The toxicities associated with these agents are largely hematological, with marrow toxicity being the major side effect of samarium Sm-153 lexidronam. A temporary increase in bone pain during early treatment occurs in 15% of patients treated with strontium-89 chloride.¹

The data for the &alpha;-particle emitter radium-223 that secured its approval came from the pivotal phase III ALSYMPCA trial.¹⁹Radium-223 is an alpha particle emitter that selectively binds to areas of increased bone turnover in bone metastases. The study randomized 921 patients in a 2:1 fashion to receive six injections of radium-223 or placebo, one injection given every 4 weeks. The primary endpoint was OS. Principal secondary endpoints included time to first SRE and biochemical endpoints. The efficacy analysis measured radium-223 survival benefit versus placebo seen at an interim analysis.

The final analysis showed median OS of 14.9 months versus 11.3 months; HR 0.70; 95% CI, 0.58-0.83;P<.001) for radium-223 and placebo respectively, which represented a 30% reduction in the risk of death for patients treated with radium-223. Radium-223 treatment significantly prolonged the time to the first SRE (median time 15.6 months vs. 9.8 months; HR 0.66; 95% CI, 0.52-0.83;P<.001). PSA blood levels at week 12 were reduced by &ge;30% in 16% of patients in the radium-223 group and in 6% of patients in the placebo group (P<.001). This was maintained for 4 weeks after the last injection in 14% versus 4% of radium-223—treated and placebo patients respectively (P<.001). Safety profiles were similar between the treatment arms. One patient experienced grade 3 febrile neutropenia in each group. There was one grade 5 hematological event (thrombocytopenia) in the radium-223 group considered possibly related to the study drug. The incidence of bone pain was reduced in patients treated with radium-223 vs placebo (10% vs 16%). Significantly more patients in the radium-223 group vs placebo experienced a meaningful improvement in QOL as determined by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) score (25 % vs 16%;P= .02).¹⁹

Future Steps

As discussed, early detection and treatment of bone metastases, possibly before symptoms occur would be ideal to reduce morbidity and mortality.^12,13Considering prostate cancer in general, the extent of the disease dictates the best timing and sequencing of treatments in addition to patient-specific factors. These include the site and extent of disease, speed of progression, symptoms experienced, comorbidities, availability of particular treatments, and AEs and contraindications of therapeutic agents/procedures.²⁰

References

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16. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy.N Engl J Med. 2014;371:424-433.

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18. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials.Eur J Cancer. 2012;48:3082-3092.

19. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer.N Engl J Med. 2013;369:213-223.

20. Ryan CJ, Saylor PJ, Everly JJ, et al. Bone-targeting radiopharmaceuticals for the treatment of bone-metastatic castration-resistant prostate cancer:&nbsp;exploring the implications of new data.Oncologist. 2014;19:1012-1018.