ASCO 2020: Discussant: Promising Therapeutic Targets in Prostate Cancer

( Following three Poster Discussion presentations assessing novel treatment approaches in advanced prostate cancer, “TRANSFORMER: Bipolar androgen therapy (BAT) versus enzalutamide (E) for castration-resistant metastatic prostate cancer (mCRPC)”, “A phase I, open-label, multicenter study to assess the safety, pharmacokinetics, and preliminary antitumor activity of AZD4635 both as monotherapy and in combination in patients with advanced solid malignancies: Results from prostate cancer patients (NCT02740985)”, and “ProCAID: A randomized double-blind phase II clinical trial of capivasertib (C) in combination with docetaxel and prednisolone chemotherapy (DP) in metastatic castration-resistant prostate cancer (mCRPC)”, Ana Aparicio, MD, provided her perspective on these emerging promising therapeutic targets in prostate cancer. However, before discussing her thoughts, here is a summary of the abstracts upon which this discussion is based.

First, in the TRANSFORMER study, Samuel Denmeade, MD, and colleagues presented the results of their randomized phase 2 trial comparing rapid cycling of testosterone using testosterone cypionate 400mg IM every 28 days (bipolar androgen therapy, BAT) or traditional androgen axis targeting therapy with enzalutamide 160mg PO daily among patients with metastatic castration-resistant prostate cancer who had progressed on abiraterone acetate. The authors assessed clinical and radiographic progression-free survival as the primary outcome and secondary outcomes including overall survival, PSA progression, objective response rate, quality of life, and adverse events. They recruited and randomized 195 men. Interestingly, the authors found similar median progression-free survival and PSA response rates for men receiving BAT and those receiving enzalutamide. By sequencing BAT before enzalutamide, there was a longer median second progression-free survival at 28.2 months, compared to 19.6 months from the reverse sequence (p=0.02). Further, BAT resulted in improved quality of life, compared to enzalutamide, and was generally well tolerated.

In the second abstract, Emerson Lim, MD, and colleagues presented the prostate cancer subgroup of a phase 1 trial assessing AZD4635 in advanced solid cancers. AZD4635 is an inhibitor of adenosine 2a receptor signaling which improves immune activation and anti-tumor activity in preclinical models. In this subset of the phase I trial, patients with refractory metastatic castration-resistant prostate cancer received either AZD4635 monotherapy (at two different doses) or AZD4635 in combination with durvalumab. In a non-randomized fashion, 49 patients received monotherapy and 45 patients received combination therapy. The majority had good performance status and the median age was 70.5 years. These patients had extensively pre-treated disease with a median number of prior treatment regimes of 5 (range 1-10), wit the majority having received prior chemotherapy (61%) and an even larger proportion having received androgen axis inhibitors (90%). Of 70 patients available for assessment, confirmed objective response rates were 6.1% in the monotherapy arm and 16.2% in the combination therapy arm. 5 patients had ongoing responses with a duration between 1 and 18.5 months. A high adenosine gene expression signature was associated with longer progression-free survival among treated patients. Adverse events including nausea, vomiting, fatigue, decreased appetite, dizziness, and diarrhea. 

Finally, Simon Crabb, MBBS, MRCP, PhD, et al. presented results from ProCAID comparing docetaxel and prednisone with or with capivasertib in patients with metastatic castration-resistant prostate cancer who had not received prior chemotherapy. Capivasertib is a pan-AKT inhibitor, a pathway commonly contributing to disease progression and chemotherapy resistance. The authors randomized 150 patients and followed them for a median of 16.8 months. They did not demonstrate benefit to the addition of capivasertib with a median PFA of 7.0 months in the experimental arm and 6.7 months in the placebo arm (hazard ratio 0.92, p-value 0.32). However, they found an improvement in overall survival among treated patients (31 months median OS) compared to those receiving placebo (20 months median OS; hazard ratio 0.54, 95% confidence interval 0.3 to 0.88, p=0.01). These results were similar in the overall cohort and in those who were biomarker positive and negative.

Dr. Aparicio reviewed each of these abstracts highlighting that, while TRANSFORMER was a “negative trial”, the authors demonstrated that BAT may resensitize prostate cancer cells to androgen and thus increase the efficacy of second-line androgen targeting agents. However, she highlights the difficulty in stratifying biologic subsets. In reviewing the ProCAID trial, she again highlighted that this is technically a negative trial due to the failure to demonstrate a difference in the primary outcome of PFS, though there is evidence of OS benefit. She highlighted that PTEN loss assays may be important in assessing the benefit of AKT inhibitors. As a result of the complexity of the PIC3K/AKT/mTOR pathway, reverse translation based on mechanistic studies may be most informative to guide the design of future trials. Finally, concerning AZD4635, Dr. Aparicio highlighted the mechanistic data highlighting the synergistic effect of adenosine mechanisms and immunotherapeutic approaches. Understanding the tumor microenvironment may allow for rational combination therapies.

Presented by: Ana Aparicio, MD, MD Anderson Cancer Center, Houston, TX

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, Twitter: @WallisCJD on Twitter at the 2020 American Society of Clinical Oncology Virtual Annual Meeting (#ASCO20), May 29th-May 31st, 2020

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Read: ASCO 2020: TRANSFORMER: Bipolar Androgen Therapy vs Enzalutamide for Castration-Resistant Metastatic Prostate Cancer