Emerging Bone-Targeted Agents That Go Beyond Palliation and May Improve Survival
Src is a member of the largest family of protein tyrosine kinases, the Src family kinases (SFKs). Src has been widely implicated through increased expression and/or activity in many visceral cancers, including prostate cancer. In addition, Src has been implicated in proliferation, invasion, and migration of prostate cancer cell lines in vitro, and may be involved in the transition from the castrate-sensitive to the castrate-resistant state.[59,60] Of further interest, Src is implicated in osteoblast differentiation and osteoclast activation, and inhibitors have demonstrated induced apoptosis of osteoclasts, reduced bone resorption, but enhanced bone-forming activity through osteoblast activity.[61,62] For an excellent overview of Src and its implications in prostate cancer, see the 2007 article by Karim Fizazi in the Annals of Oncology.
A phase II study of dasatinib(Drug information on dasatinib) (Sprycel) monotherapy in 47 patients with chemotherapy-naive CRPC reported lack of progression in 43% of patients at week 12 and in 19% at week 24, reductions in uNTx and bone-specific alkaline phosphatase (ALP) levels in a majority of patients, and achievement of a PSA decline of ≥ 50% in three patients.[64-66] Dasatinib and other Src inhibitors are interesting in that this class of pharmaceuticals theoretically has both direct anti-tumor effects (evidenced by lack of progression, regression, and/or PSA declines) and bone-targeted mitigation of the deleterious effects of metastases. Although this phase II study demonstrated both these effects, only changes in bone-turnover markers were reported, not clinical outcomes such as SREs or overall survival. Other studies, however, have shown a positive correlation of these markers with clinical outcomes.
A phase I/II study combining dasatinib with docetaxel(Drug information on docetaxel) in patients with metastatic CRPC showed a PSA response in 41% and an objective tumor response in 57% of patients with measurable disease. One third of patients experienced an improvement of disease on bone scan, and two thirds had stable disease in bone for ≥ 6 weeks. A randomized phase III trial of docetaxel and prednisone(Drug information on prednisone) with or without dasatinib (NCT00744497) is ongoing, with a primary endpoint of overall survival.
In summary, Src kinase inhibitors offer the potential for direct antitumor activity and bone-targeted therapy, although clinical outcomes with respect to SREs have yet to be reported. This class of drugs has been evaluated as monotherapy in chemotherapy-naive patients and is undergoing further study in combination with docetaxel. While there are other Src inhibitors in development, only saracatinib (previously referred to as AZD0530) is currently being studied in prostate cancer.[69,70] Phase II trials of this drug are currently in the recruitment phase.
Endothelin-A receptor antagonists
The endothelin pathway has been implicated in the development and progression of PCa. Endothelins modulate vasomotor tone, nociception, cell proliferation, and angiogenesis; in addition, endothelins bind two receptors, endothelin-A and endothelin-B. Patients with metastatic CRPC have been noted to have elevated levels of endothelin-1 in plasma compared with patients with nonmetastatic disease. In addition to their involvement with PCa tumor cells, there is evidence that endothelins are involved in osteoblastic bone turnover activity.[71,72] Inhibitors of the endothelin receptors have thus been studied clinically in the setting of nonmetastatic and metastatic CRPC.
Atrasentan. Atrasentan (Xinlay) is primarily an endothelin-A antagonist. Initial, phase II study data comparing a 10-mg oral daily dose of atrasentan to placebo in 288 patients with asymptomatic, metastatic CRPC found encouraging results: there was a statistically significant longer median time to progression with atrasentan (196 vs 129 days; P = .021). Median time to PSA progression was also longer with atrasentan than with placebo (155 vs 71 days; P = .002). At 180 days, only 35% of placebo-treated patients were free from progression of disease, but 54% of atrasentan-treated patients were still free from progression. Serum markers (lactate dehydrogenase and alkaline phosphatase) were not significantly different between the two groups.
Based on these promising data, phase III trials were conducted in patients with nonmetastatic CRPC and in patients with metastatic CRPC.[74,75] Neither trial demonstrated any difference in time to progression between the atrasentan and placebo groups, but there were significant differences in serum bone turnover markers and PSA levels. In the nonmetastatic CRPC trial, there was a trend towards prevention of progression to skeletal metastasis, but this did not reach significance. Bone pain was not significantly different between the two groups in the metastatic CRPC trial, but a subset analysis of patients with bone metastases at baseline (59%) suggested a greater delay in time to progression. Thus, it has been suggested that this drug class may provide more benefit in patients with bone disease.
Zibotentan. Another endothelin-A receptor antagonist, zibotentan (or ZD4054), has undergone testing in phase I and II studies. A phase II study randomly assigned patients with metastatic CRPC to receive placebo or zibotentan; study investigators found that time to progression was not different between the two groups, but overall survival was significantly different (23.5 months vs 17.3 months; HR, 0.65 [80% CI, 0.49–0.86]; P = .052). Final analysis demonstrated that there were fewer new metastases to bone with 10 mg zibotentan than with placebo (treatment ratio, 0.83; 80% CI, 0.70–0.98; P = .155), but this was not seen with 15-mg dosing (although the latter cohort did have a slightly higher number of baseline bony metastases).
Currently, there are multiple phase III trials underway for both atrasentan and zibotentan as combination therapy with docetaxel in patients with metastatic CRPC; primary outcomes are progression-free survival and overall survival.[77-79] Some survival advantage with this class of drugs and trends towards increased efficacy in patients with metastatic lesions to bone have been seen; we await the final results of the combination trials for final assessment of these drugs with respect to treatment of bony disease, pain, and progression of disease.
Clusterin functions as a cytoprotective chaperone protein that is upregulated with therapy-induced cell stress; clusterin has been identified as a potential therapeutic target in CRPC. OGX-011 (Custersin) is complementary to the clusterin mRNA translation initiation site, thereby inhibiting its translation into function product. A randomized controlled trial comparing docetaxel plus prednisone with or without OGX-011 in the treatment of patients with metastatic CRPC demonstrated promising results. Overall survival was 23.8 with OGX-011 vs 16.9 months without OGX-011 (HR, 0.50; 95% CI, 0.29-0.87). A second randomized controlled trial examined OGX-011 in combination with docetaxel or mitoxantrone(Drug information on mitoxantrone) as second-line therapy in patients with metastatic CRPC after progression on docetaxel therapy. Overall survival was 15.8 months in the docetaxel plus OGX-011 arm vs 11.5 months in the mitoxantrone plus OGX-011 arm, comparing favorably to cabazitaxel. Phase III studies of OGX-011 are underway, with one exploring survival as a primary endpoint and another examining pain palliation.[83,84]
Alpha particles consist of two protons and two neutrons, similar to a helium nucleus. They are highly ionizing and have low penetration depth, affecting only nearby tissues and limiting toxicity. There is currently only one alpha-emitting radionuclide under investigation, radium-223 (223Ra; Alpharadin).
Initial phase I data, published in 2005, included 15 PCa and 10 breast cancer patients. Each patient received a single dose of 223Ra, with the doses ranging in intensity from 46 to 250 kBq/kg. Grade 3 neutropenia and leucopenia occurred in two and three patients, respectively. Ten of the 25 patients experienced transient diarrhea. Nausea and vomiting were more frequently observed in the highest dosage group. Notably, pain relief was reported by 52%, 60%, and 56% of the patients after 7 days, 4 weeks, and 8 weeks, respectively. 223Ra was noted to clear rapidly from blood and was below 1% of initial level at 24 hours. Excretion was primarily gastrointestinal (GI), accounting for the GI-related side effects.
Another phase I dose-escalation study involved 10 men with progressive CRPC with more than two bone metastases; the patients were treated in three cohorts, with dose levels of 50, 100, and 200 kBq/kg. Patients received one treatment at the cohort-defined dose, followed by one optional treatment 6 weeks later at 50 kBq/kg. This study demonstrated no dose-related toxicities. 223Ra accumulated in bone metastases within the first 10 minutes of injection. Three patients suffered grade 3 hematologic toxicities, which were not related to dose level. 223Ra was well tolerated at doses up to 200 kBq/kg.
Another study examined dosimetry and biodistribution of 223Ra in six patients with CRPC and bone metastases. Doses of absorbed radiation were calculated for various tissues: red marrow, 0.23 Gy/MBq; and lower large intestine wall, 0.05 Gy/MBq. As decaying alpha particles are released from 223Ra, their short range (< 100 µm) affects only a small volume of red marrow, likely accounting for a favorable safety profile even in patients with extensive skeletal metastatic disease.
Phase II data from a larger cohort of patients were published in Lancet Oncology in 2007. Thirty-three patients were randomly assigned to receive 4 IV injections of 223Ra (50 kBq/kg), and 31 were randomly assigned to receive placebo. Primary endpoints included changes in bone ALP and time to an SRE. Secondary endpoints consisted of side-effect profile, time to PSA progression, and overall survival. ALP declined 66% relative to baseline in the 223Ra-treated patients, whereas it increased 9% in the patients who received placebo (P < .0001). Hazard ratio for time to SRE was 1.75, but significance was not achieved (95% CI, 0.96-3.19; P = .065). Time to PSA progression was 26 weeks for 223Ra vs 9 weeks for placebo. Overall survival was 65 weeks for the treatment group vs 46 weeks for the control group (P = .066), but after adjusting for baseline patient characteristics, this became significant (P = .020). The bone-targeted effects were significant, yet there was minimum myelotoxicity (no difference was noted between the two groups).
On the basis of these results, a phase III randomized controlled trial with 922 patients was started. Investigators randomly assigned the patients in a 2:1 ratio to receive 223Ra or placebo, in addition to standard care. Each patient randomized to 223Ra received injections every 4 weeks for 6 total doses. The primary endpoint was overall survival. Results have not yet been published, but very recently, investigators announced that the trial was going to halt early after a planned interim analysis. The data safety monitoring board noted a 30% reduction in the odds of dying during follow-up in the 223Ra treatment arm, and a median increase in overall survival of 3 months. Four percent of patients were noted to have suffered hematologic toxicity (2% grade 3/4), and 8% suffered thrombocytopenia (4% grade 3/4).
Cytotoxic therapies such as docetaxel and cabazitaxel have been shown to have proven benefit and potential. They are, however, limited by the development of resistance and systemic toxicities. Treatment with other agents after the development of resistance is not well defined, although some of the other drugs discussed in this review may ultimately be of use for patients with chemotherapy-resistant CRPC. In a future article, we will deal with the important challenges of sequencing the many new therapies for CRPC.
Despite an explosion in the number of agents under investigation for the treatment of CRPC, very few offer direct efficacy against metastatic disease spread to the bone. As stated, bony metastasis accounts for a great deal of morbidity and mortality. Palliation is an important aspect of treatment, and some interventions have also shown success in mitigating SREs. Systemic chemotherapy is likely to remain the mainstay of treatment for CRPC in the years to come, with therapies such as those discussed here used as adjunctive treatments to achieve specific clinical aims.
Endothelin-A receptor antagonists may have some activity against tumor in bone, but single-agent studies do not show any evidence of benefit, and it remains unclear whether endpoints other than those reported might be associated with positive results. Nevertheless, these agents are currently under study in combination with other proven therapies for CPRC in the hope of realizing synergistic outcomes. We await these results.
Among agents that specifically target bone, alpha pharmaceuticals offer particular promise for activity and safety in men with bony metastasis. Investigators have finished phase I and II studies, and recently ended phase III study early after the safety monitoring board found a significant increase in overall survival in patients receiving 223Ra compared with those receiving placebo. In a future article, we hope to review in detail the development and clinical activity of this agent. There are ongoing studies examining 223Ra in combination with docetaxel. If approved for use, it remains to be seen in which patient population and following which other therapies alpha pharmaceuticals might be most appropriate. Given the plethora of agents now available to clinicians, the choice will likely depend largely on the comfort of the physician with the administration of a given therapy (radiopharmaceuticals require extra safety and training) and on discussion with the patient.
For many years, docetaxel chemotherapy was the only treatment that showed a true survival advantage for men with CRPC. Now, entire new classes of drugs aim to treat and target disease, palliate symptomatic pain, and prevent SREs. These represent dramatic new advances in the field of urologic oncology and promise a real therapeutic advantage in the treatment of CRPC and bony metastases. Treating physicians will be faced with significant challenges in determining the sequencing of these new agents.
Financial Disclosure: Dr. Crawford serves on advisory boards for Ferring, sanofi aventis, Bayer, Amgen, and Dendreon; also, a member of his family is an employee of Ferring. Dr. Rove has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.