ESMO 2017: 14 years of progress in mCRPC – New avenues for immunotherapy and precision medicine: Invited Discussant

Madrid, Spain (UroToday.com) Dr. Ronald De Wit concluded the prostate cancer poster discussion session with an invited discussant presentation assessing four high-level abstracts presented at ESMO 2017 in Madrid, Spain. The four posters included “Safety and Immunogenicity of a DNA-vaccine Immunotherapy in Men with Biochemically (PSA) Relapsed Prostate Cancer” by Dr. Neal Shore, “Re-education of tumor-associated macrophages by CXCR2 blockade drives senescence enhancement and tumor inhibition in advanced prostate cancer” by Dr. Diletta Di Mitri, “Phase I, Open-label, Dose-Finding Study of GSK2636771, a phosphoinositide 3-kinase β inhibitor, in Combination with Enzalutamide in Male Subjects with Metastatic Castration-Resistant Prostate Cancer” by Pasquale Rescigno and “Phase I study of the PSMA-targeted small-molecule drug conjugate EC1169 in patients with metastatic castrate-resistant prostate cancer” by Dr. Michael Morris.

Dr. Shore’s study found the DNA vaccine INO-5150 +/- INO-9012 was safe at the dosages examined. The data demonstrated that both PSA and PSMA are immunogenic and INO-5150 induced cellular immune responses. A higher proportion of Arm A patients showed immunological responses, as well as improvements in PSA doubling time, specifically patients with PSA doubling time ≤ 12 months, suggesting correlation of immunological efficacy and clinical benefit. Dr. De Wit notes several important findings from this study, (i) there were no safety concerns, considering that most adverse events were associated with injection site reactions, (ii) immune reactivity was observed for both PSA and PSMA antigens, and (iii) in the setting of expression of PD1, activation markers, and lytic proteins on CD8+ T cells there was increased reactivity against INO-5150 antigens increased over baseline in 39% of patients.

Dr. Di Mitri’s study found that re-education of tumor-associated macrophages by CXCR2 blockade drives senescence enhancement and tumor inhibition in advanced prostate cancer, suggesting that TAMs may be a future target for prostate cancer therapy. Dr. De Wit notes that this is a novel mechanism by which CXCR2 antagonists exert an antitumor response, particularly for PTEN deletion tumors which appear to be quite sensitive. In his opinion, future clinical trials evaluating the efficacy of CXCR2 antagonists should stratify for the level of PTEN.

Dr. Rescigno’s study found that based on preliminary data, the potent adenosine triphosphate (ATP) competitive, selective, oral inhibitor of the phosphoinositide 3-kinase β (PI3Kβ) isoform GSK2636771 in combination with enzalutamide is largely well tolerated and confirm the clinical relevance of PI3Kβ inhibition in PTEN-deficient mCRPC. Dr. De Wit highlights the importance of no safety issues in this exciting phase I study and the fact in one patient there was a partial response with continued therapy to 35 weeks. Ultimately, he feels that this PI3Kβ inhibitor has potential to be clinically relevant, particularly in PTEN deletion tumors, and thus warrants further study.

Dr. Morris’ study found that the dose of EC1169 6.5 mg/m2, a PSMA-targeted conjugate of the microtubule inhibitor tubulysin B hydrazide, is well tolerated among the first 34 patients treated. This PSMA-targeted therapeutic strategy appears viable, with evidence of anti-tumor activity in both the taxane naïve and taxane exposed patients. Once again, with any phase I study, Dr. De Wit highlights the lack of safety concerns, with the additional note that EC1169 resulted in alkaline phosphatase declines in these high-risk patients. However, in his opinion, this study highlights the heterogeneity of mCRPC, considering that 43% of patients were PSMA positive, yet circulating tumor cell negative.

Speaker: Ronald De Wit, Erasmus MC-Cancer Institute, Rotterdam, Netherlands

Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain

References:

1. Shore ND, Heath E, Nordquist L, et al. Safety and Immunogenicity of a DNA-vaccine Immunotherapy in Men with Biochemically (PSA) Relapsed Prostate Cancer. ESMO 2017 abstr 790.
2. Di Mitri D, Vasilevska J, Calcinotto A, et al. Re-education of tumor-associated macrophages by CXCR2 blockade drives senescence enhancement and tumor inhibition in advanced prostate cancer. ESMO 2017 abstr 791.
3. Rescigno P, de Bono J, Aparicio A, et al. Phase I, Open-label, Dose-Finding Study of GSK2636771, a phosphoinositide 3-kinase β inhibitor, in Combination with Enzalutamide in Male Subjects with Metastatic Castration-Resistant Prostate Cancer. ESMO 2017 abstr 792.
4. Morris M, Vogelzang NJ, Sartor O, et al. Phase I study of the PSMA-targeted small-molecule drug conjugate EC1169 in patients with metastatic castrate-resistant prostate cancer. ESMO 2017 abstr 793.
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