BERKELEY, CA (UroToday.com) - The progression to castration-resistant prostate cancer (CRPC) marks a clinical acceleration of disease associated with a poor outcome. First-line treatment for CRPC typically consists of 3-week docetaxel in combination with prednisone.[1]
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"Results from this trial demonstrate that treatment with Ridaforolimus (50-mg dose) administered intravenously once weekly did not produce objective responses...by blocking mTOR signaling in the PI3K/Akt/mTOR pathway, patients treated with Ridaforolimus may achieve only stable disease." |
Other treatment regimens for CRPC patients include 3-week docetaxel and estramustine and 3-week mitoxantrone and prednisone.[1] Despite high response rates to these regimens, patients eventually develop progressive disease (PD), with a median time to progression of 6 to 8 months and a median survival time of only 17 to 19 months.[2, 3, 4] Cabazitaxel and abiraterone acetate are recommended as a second-line treatment for CRPC.[1] However, no consensus exists regarding the best approach after docetaxel failure; current options include second-line hormonal therapy, taxane-based thereapy, or immunotherapy. There is a continued need for additional therapies in this setting, with targeted therapy representing a potentially viable option.
Multiple genetic alterations have been associated with the development of CRPC, including loss of the tumor suppressor phosphatase and tensin homolog (PTEN), amplification of protein kinase B (Akt), and, less frequently, mutations of phosphatidylinositol 3-kinase (PI3K).[5, 6, 7] Preclinical studies show that mammalian target of rapamycin (mTOR) inhibitors suppress proliferation of aggressive CRPC cell lines and also act either additively or synergistically with taxanes and antiandrogens in prostate cancer models.[8, 9, 10, 11, 12, 13, 14, 15] The mTOR inhibitor RAD001 (everolimus) was shown to reverse Akt-dependent prostate intraepithelial neoplasia in a murine model in which human AKT1 was expressed in the ventral prostate. These observations suggest that agents targeting the PI3K/Akt/mTOR pathway might be effective in CRPC and might restore sensitivity to taxanes and/or antiandrogens.
Ridaforolimus (AP23573, MK-8669, formerly deforolimus; Merck&Co, Inc./ARIAD Pharmaceuticals, Inc.) is an mTOR inhibitor that has been shown to reduce cancer cell proliferation in both in vitro and in vivo experimental models.[16] In phase I trials, Ridaforolimus was well tolerated by patients with advanced malignancies.[17, 18] Results from these trials provided preliminary evidence of clinical benefit, typically reflected by disease stabilization. The present phase II trial was designed to assess the antitumor activity, safety, and tolerability of once-weekly Ridaforolimus in patients with taxane-treated CRPC.
Male patients aged 18 years or older with histologically documented adenocarcinoma of the prostate were eligible if they were clinically refractory to hormone therapy (orchiectomy or luteinizing hormone-releasing hormone agonist/antagonist) and had progressive disease after a cytotoxic chemotherapy regimen. Eligibility also required metastatic disease with either measurable lesions or prostate-specific antigen (PSA) 5 ng/mL or greater; previous treatment with at least 1 taxane-containing regimen and not more than 3 additional cytotoxic drug regimens; and previous orchiectomy or maintenance of castrate levels of testosterone less than 50 mg/dL by luteinizing hormone-releasing hormone agonist/antagonist therapy.
In this open-label phase II study, the mTOR inhibitor Ridaforolimus was administered at a dose of 50 mg intravenous once weekly to 38 patients with taxane-treated CRPC. The primary end point was best overall response according to modified Response Evaluation Criteria in Solid Tumors guidelines. Serum prostate-specific antigen levels were prospectively monitored as a biomarker for cancer activity.
For the primary efficacy end point, best overall response rate, all 38 patients who received at least 1 dose of Ridaforolimus were considered for assessment. Fourteen patients (36.8%) could not be assessed for best overall response because they did not have target lesions that met measurable criteria. No objective responses were observed: 18 patients (47.4%) had stable disease as their best overall response, whereas 5 patients (13.2%) demonstrated PD and 1 patient was not evaluable. Patients assessed by computed tomography scan, magnetic resonance imaging, and/or bone scans were determined to have stable disease if the criteria were met after a minimum interval of 8 weeks from the start of treatment. Progression-free survival, analyzed as one of the secondary endpoints, demonstrated a median PFS of 28 days (95% confidence interval, 27–29) in the cohort of patients in this study treated with Ridaforolimus. Of note, for PFS analysis, patients were considered to have progressed based on either radiologic evidence assessed by RECIST, or increases in PSA levels.
Changes in serum PSA were also analyzed as a secondary efficacy end point for all 38 patients enrolled in the trial with baseline PSA of 5 ng/mL or greater. Eight patients (21.1%) had stable disease as their best overall PSA response, whereas 23 patients (60.5%) had PSA progression. PSA responses could not be evaluated or assessed in the other 7 patients. Treatment-emergent AEs (TEAEs) were reported by all 38 patients who received at least 1 dose of Ridaforolimus. The most common were anemia, thrombocytopenia, neutropenia, fatigue, mucosal inflammation, nausea, peripheral edema, rash, diarrhea, and constipation. Grade 3 to 4 hematologic (e.g., thrombocytopenia, neutropenia) and nonhematologic (e.g., fatigue, hypertriglyceridemia, hyperglycemia, hypokalemia) TEAEs were also reported with Ridaforolimus treatment.
Results from this trial demonstrate that treatment with Ridaforolimus (50-mg dose) administered intravenously once weekly did not produce objective responses. Stable disease was observed in some patients with taxane-treated CRPC. Ridaforolimus was generally well tolerated in this patient population, with a safety profile similar to that observed in patients with advanced malignancies. By blocking mTOR signaling in the PI3K/Akt/mTOR pathway, patients treated with Ridaforolimus may achieve only stable disease. Future clinical trials in patients with CRPC could assess the benefit and safety profile of Ridaforolimus in combination with other chemotherapies (e.g., taxanes or targeted agents). Trials exploring new treatment paradigms for CRPC may also be considered with mTOR inhibitors, such as Ridaforolimus.
References:
- NCCN clinical practice guidelines in oncology: prostate cancer: National Comprehensive Cancer Network.
- Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351(15): 1513-20.
- Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. Journal of Clinical Oncology: official journal of the American Society of Clinical Oncology 2008; 26(2): 242-5.
- Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351(15): 1502-12.
- Garcia JA, Danielpour D. Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies. Mol Cancer Ther 2008; 7(6): 1347-54.
- Rai JS, Henley MJ, Ratan HL. Mammalian target of rapamycin: a new target in prostate cancer. Urologic Oncology 2010; 28(2): 134-8.
- Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010; 18(1): 11-22.
- Fung AS, Wu L, Tannock IF. Concurrent and sequential administration of chemotherapy and the Mammalian target of rapamycin inhibitor temsirolimus in human cancer cells and xenografts. Clinical cancer research : an official journal of the American Association for Cancer Research 2009; 15(17): 5389-95.
- Ghosh PM, Malik SN, Bedolla RG, et al. Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation. Endocr Relat Cancer 2005; 12(1): 119-34.
- Kinkade CW, Castillo-Martin M, Puzio-Kuter A, et al. Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. The Journal of Clinical Investigation 2008; 118(9): 3051-64.
- Kobayashi T, Shimizu Y, Terada N, et al. Regulation of androgen receptor transactivity and mTOR-S6 kinase pathway by Rheb in prostate cancer cell proliferation. The Prostate 2010; 70(8): 866-74.
- Morgan TM, Pitts TE, Gross TS, Poliachik SL, Vessella RL, Corey E. RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid. The Prostate 2008; 68(8): 861-71.
- Wang Y, Mikhailova M, Bose S, Pan CX, deVere White RW, Ghosh PM. Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival. Oncogene 2008; 27(56): 7106-17.
- Wu L, Birle DC, Tannock IF. Effects of the mammalian target of rapamycin inhibitor CCI-779 used alone or with chemotherapy on human prostate cancer cells and xenografts. Cancer Research 2005 65(7): 2825-31.
- Zhang W, Zhu J, Efferson CL, et al. Inhibition of tumor growth progression by antiandrogens and mTOR inhibitor in a Pten-deficient mouse model of prostate cancer. Cancer Research 2009; 69(18): 7466-72.
- Mita M, Sankhala K, Abdel-Karim I, Mita A, Giles F. Deforolimus (AP23573) a novel mTOR inhibitor in clinical development. Expert Opinion on Investigational Drugs 2008; 17(12): 1947-54.
- Mita MM, Mita AC, Chu QS, et al. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. Journal of Clinical Oncology: Official journal of the American Society of Clinical Oncology 2008; 26(3): 361-7.
- Hartford CM, Desai AA, Janisch L, et al. A phase I trial to determine the safety, tolerability, and maximum tolerated dose of deforolimus in patients with advanced malignancies. Clinical Cancer Research: An official journal of the American Association for Cancer Research 2009; 15(4): 1428-34.
Written by:
Robert J. Amato, DO as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
The University of Texas Health Medical School, Memorial Hermann Cancer Center, Houston, TX USA
