Recent Advances Revolutionize Treatment of Metastatic Prostate Cancer

Ravi A Madan; Philip M Arlen

Disclosures

Future Oncol. 2013;9(8):1133-1144. 

In This Article

Other Emerging Therapies

Alpharadin®

Additional treatment strategies are also in development for the treatment of mCRPC (Table 3). Radiopharmaceuticals have been used clinically for some time. Strontium-89 and samarium-153 have been used as palliative treatments for patients with bone metastases, while ibritumomab tiuxetan (Zevalin®; Spectrum Pharmaceuticals, CA, USA), a radiotherapeutic antibody, has demonstrated clinical efficacy in lymphomas.[62–64] Radium-223 (Alpharadin®; Algeta, Oslo, Norway) is an α-radiation-emitting agent, which differentiates it from strontium-89 and samarium-153, which emit γ- and β-particles. The significance of this is that α-particles carry higher radioactive energy but travel shorter distances (<100 µm), allowing for greater potential lethality to cancer cells but less toxicity to normal tissue beyond the tumor microenvironment. Perhaps most significant is that, unlike samarium-153 and strontium-89, there is less myelosuppression with radium-223.[65]

A recent Phase III study evaluated radium-223 and best supportive care compared with placebo and best supportive care in men with mCRPC, at least two bone metastases and no visceral disease.[66] The study, which included both docetaxel-treated and -naive patients, randomized 922 men 2:1 in favor of radium-223 and was designed with OS as its primary end point. The results indicated improved survival for patients treated with radium-223, with a median OS of 14 versus 11.2 months for placebo (HR: 0.695; p = 0.00185). Furthermore, in patients treated with radium-223 the time to first skeletal-related morbidity was significantly delayed (median: 13.6 vs 8.4 months; HR: 0.610; p = 0.00046). It is anticipated that these findings will be sufficient to lead to FDA approval, giving oncologists a radiopharmaceutical with palliative properties, less myelosuppression and the possibility of improved survival.

Cabozantinib

Cabozantinib is a promising dual tyrosine kinase inhibitor that targets both the mesenchymal–epithelial transition and VEGFR2, both of which are implicated in the progression of prostate cancer.[67,68] Previous tyrosine kinase and VEGF inhibitors have failed to enhance clinical outcomes in mCRPC, but striking findings in early-phase trials of cabozantinib have drawn significant attention.[4,69]

In a randomized discontinuation study, 171 patients with mCRPC were initially treated for 3 months with cabozantinib, then randomized to continue the drug or receive a placebo. Median progression-free survival for the 31 patients randomized after 3 months was 23.9 weeks for those on cabozantinib compared with 5.9 weeks for those on placebo.[70] Even more noteworthy was the objective response rate after 3 months among all patients treated: 75% had stable disease and 5% had responses, while 72% had regression of soft tissue lesions and 68% had improvements on bone scan. Improvements on bone scan are rarely seen with other treatments for mCRPC, and certainly not on this scale. The apparent improvements in bone metastasis were accompanied by improvements in pain symptoms in 67% of patients and improvement in serum markers associated with bone lesions (alkaline phosphatase and c-telopeptide). These associations between serum marker changes and symptom improvement suggest that the impact of cabozantinib on the bone/tumor microenvironment is genuine and not just an artefact of the drug's impact on imaging studies.

Based on these promising results, the study was discontinued early so that additional studies could be initiated. Fatigue, decreased appetite and a spectrum of gastrointestinal symptoms (nausea, diarrhea and constipation) were seen in more than half of the patients. For this reason, a recent study evaluated cabozantinib at a lower dose (40 mg compared with 100 mg in the discontinuation study) and found that the drug was better tolerated with similar clinical effect.[71] Based on these findings, a Phase III study has been launched in mCRPC patients who have received docetaxel, comparing cabozantinib to mitoxantrone and prednisone.[111]

These emerging data of cabozantonib's potential anti-tumor effects in bone lesions combined with potential therapeutic and palliative effects of Alpharadin are of great potential clinical importance. Together with previous data that suggest the rank-ligand inhibitor denosumab may delay bone metastasis, there may finally be meaningful progress in addressing the primary metastatic site for most prostate cancer patients.[72] A better understanding of the bone (tumor) microenvironment may have palliative effects in the short term, but could limit metastatic disease in the long term if the underlying mechanisms that promote bone metastasis are better understood.

Tasquinimod

Tasquinimod is another emerging agent with antiangiogenic properties. This treatment is a quinolone-3-carbozamide that has previously demonstrated preclinical evidence of anti-tumor activity in prostate cancer.[73,74] It has been shown to decrease angiogenesis, perhaps through the inhibition of genes that can be induced by hypoxia. Furthermore, it has been found to be a potent inhibitor of S1900A9, which is expressed in the tumor microenvironment and on myeloid-derived suppressor cells, which have been implicated in immune suppression.[75] Suppression of immune responses may be important since it creates a more permissive environment for tumor growth.[76]

Phase I studies of tasquinimod enrolled 32 chemotherapy-naive CRPC patients. The most common adverse events included inflammation, nausea and fatigue. Rare but serious adverse events included sinus tachycardia, cerebral infarction and hyperamylasemia.[77] A subsequent randomized Phase II trial randomized 134 minimally symptomatic mCRPC patients 2:1 to tasquinimod or placebo. Although there were no significant changes in PSA progression in the two arms of the trial, clinical (pain) or radiographic progression-free survival favored the tasquinimod arm (7.6 vs 3.3 months; p = 0.0042).[78] Currently, a Phase III study of tasquinimod versus placebo is enrolling mCRPC patients in order to determine its true efficacy in mCRPC.[112]

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