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Phase I/II Study Evaluating the Safety and Clinical Efficacy of Temsirolimus and Bevacizumab in Patients with Chemotherapy Refractory Metastatic Castration-Resistant Prostate Cancer – Beyond the Abstract

The management of patients with metastatic prostate cancer continues to be complex and challenging despite the treatment advances that occurred in the last few years. Until 2015, most patients with initial diagnosis of metastatic prostate cancer (de-novo) were treated with androgen deprivation therapy (ADT) but now adding docetaxel or abiraterone/prednisone to ADT has become standard of care (SOC) since studies have shown a survival benefit with both of these agents. Unfortunately, over a period of time, most men undergoing these treatments become resistant as evidenced by rising PSA, a clinical and radiological progression of the disease called castration-resistant prostate cancer (CRPC).

Multiple pathways are known to cause this resistance leading to the progression of cancer. The phosphatidylinositol 3-kinase (PI3K)-Akt – mTOR pathway, which is deregulated in the majority of advanced prostate cancer patients is known to play a major role in the development and maintenance of CRPC4.5. Proangiogenic factor like VEGF is also known to play an important role in tumor angiogenesis, tumor cell proliferation, and bone destruction in patients with advanced prostate cancer6,7. Expression of VEGF has been upregulated in prostate cancer7. Few clinical trials have shown that mTOR pathway inhibitor, temsirolimus 8 and VEGF inhibitor, bevacizumab9 when used as monotherapy have modest clinical activity in prostate cancer but not many studies have been done to see the outcomes after combining both these agents.

In our study published in Investigational new drugs (Barata 2018) we have assessed the potential synergistic activity of dual inhibition of mTOR and VEGF pathway in patients with mCRPC. This is a phase I/II trial done on 24 patients with median age of 64 and pre-treatment PSA of 205.3 where we have assessed the safety and clinical efficacy of bevacizumab given 10 mg every 2 weeks and temsirolimus given weekly at 20 or 25 mg, previously treated with median of 2 lines of therapy for chemotherapy-refractory metastatic castration-resistant prostate cancer. Median time to progression was 2.6 months and the median best PSA change from baseline to 12 weeks was a 32% increase which met the predefined futility rule and led to early termination of the study. Nine patients (43%) had ≥ grade 3 toxicity that included fatigue (24%), anorexia (10%), nausea/vomiting (5%) and lymphopenia (5%). In an exploratory analysis, a decrease in circulatory tumor cells level (CTC) was observed in 9 out of 11 patients. No association between PSA levels and CTC levels was detected. 

Our study is one of the first to assess the safety and efficacy of mTOR inhibitor in combination with VEGF inhibitor in mCRPC patients. The inhibition of these two pathways has demonstrated interesting clinical activity in other solid tumors and is currently approved for the treatment of advanced RCC (lenvatinib+ everolimus)10.

The findings of our study are concurrent with previous studies wherein mTOR or VEGF inhibitor used as monotherapy in a similar setting showed only transient PSA response without any meaningful survival benefit 8,9. The toxicity profile of the combination used in our study was also a major disadvantage as almost half of the patients suffered from significant toxicities. These findings compare similarly with previous studies combining everolimus with anti-VEGF therapy in patients with RCC10,11 Surprisingly, the changes in the levels of CTC and PSA in our study did not correlate to predict the outcomes as opposed to previous studies wherein CTC levels were found to be better prognostic indicator than PSA12,13

Given the lack of meaningful clinical activity and significant toxicities from the combination of temsirolimus and bevacizumab in mCRPC patients, it would be justified to not use this combination in this setting. Further clinical trials are needed to investigate the targets of tumor resistance and therapies to treat them without causing significant toxicities to the patient.

Written by: Ruby Gupta, MD1, Jorge Garcia, MD1, Pedro Barata, MD, MSc2
1. Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA
2. Assistant Professor, Tulane Medical School, Department of Internal Medicine, Section of Hematology and Medical Oncology, New Orleans, Louisiana, USA

References:
  1. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomized controlled trial. Lancet 2016; 387: 1163-77.
  2. Sweeney CJ, Chen Y-H, Carducci M, et al. Chemo hormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015; 373: 737-46
  3. Sartor O, de Bono JS (2018) Metastatic prostate cancer. N Engl J Med 378(7):645–657
  4. Merritt P Edlind and Andrew C Hsieh. PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance. Asian J Androl. 2014 May-Jun; 16(3): 378–386
  5. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18(16):1926–1945
  6. Botelho F, Pina F, Lunet N. VEGF and prostatic cancer: a systematic review. Eur J Cancer Prev. 2010 Sep;19(5):385-92
  7. Duque JL, Loughlin KR, Adam RM, Kantoff PW, Zurakowski D, Freeman MR (1999) Plasma levels of vascular endothelial growth factor are increased in patients with metastatic prostate cancer. Urology 54(3):523–527
  8. Kruczek K, Ratterman M, Tolzien K, Sulo S, Lestingi TM, Nabhan C (2013) A phase II study evaluating the toxicity and efficacy of single-agent temsirolimus in chemotherapy-naive castration-resistant prostate cancer. Br J Cancer 109(7):1711–1716
  9. McKay RR, Zurita AJ, Werner L et al (2016) A randomized phase II trial of short-course androgen deprivation therapy with or without bevacizumab for patients with recurrent prostate Cancer after definitive local therapy. J Clin Oncol 34(16):1913–1920
  10. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-1482
  11. Rini BI, Bellmunt J, Clancy J et al (2014) Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol 32(8):752–759
  12. De Bono JS, Scher HI, Montgomery RB et al (2008) Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 14(19):6302–6309
  13. Scher HI, Jia X, de Bono JS et al (2009) Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncol 10(3):233–239
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