(UroToday.com) In this presentation, Dr. Ana Aparicio provided a discussion on the following three abstracts representing promising treatment strategies under development in prostate cancer.
Abstract 5517 – TRANSFORMER: Bipolar androgen therapy versus enzalutamide for castration-resistant metastatic prostate cancer
Over sixty years ago, case reports emerged of rare patients with metastatic prostatic cancer who experienced symptomatic and laboratory metric improvements after treatment with testosterone. Subsequent small clinical studies and preclinical work have suggested that testosterone therapy may have a unique role in sensitizing prostate cancers that have progressed on anti-androgen therapy to second-line anti-androgen therapy. Bipolar androgen therapy (BAT) specifically refers to patients on androgen-deprivation therapy (ADT) receiving monthly injections of 400 mg of testosterone cypionate, which cause transient supraphysiologic levels of serum testosterone in excess of 1500 mg/dL, then a subsequent reduction in serum testosterone levels to castrate levels (< 50 ng/dL).
In this study, patients with metastatic castration-resistant prostate cancer (mCRPC) on ADT that progressed on abiraterone were randomized to BAT or enzalutamide, with the option to crossover to the alternative therapy once clinical or radiographic progression was noted. Patients in the BAT arm had favorable safety profiles, with less fatigue, insomnia, nausea, diarrhea, and hot flashes relative to patients on enzalutamide. Though there were no significant differences between clinical/radiographic or prostate-specific antigen (PSA) response rates in the initial randomization, patients receiving initial BAT then enzalutamide had a longer time to PSA progression and PFS2 relative to patients receiving initial enzalutamide then BAT. These data are provocative, but additional work is required to suggest which patients may actually benefit from BAT.
Abstract 5518– 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
Extracellular adenosine accumulates in hypoxic tumor environments and is associated with decreased immune response. This immune suppression is thought to be in part due to adenosine binding to the T-cell adenosine 2A receptor (A2aR). There is interest in targeting the A2aR based on data showing A2aR upregulation in response to treatment with the anti-PD-L1 antibody durvalumab, and data showing enhanced T-cell activation with combination PD1/PDL1 and A2aR axis therapy. This abstract presented data as part of a larger multi-center Phase I trial in multiple cancers looking at AZD4635 monotherapy or in combination with specific agents across multiple cancer types. The trial utilizes a Bayesian logistic regression model-based approach in its design.
In prostate cancer patients, AZD4635 was administered as monotherapy or in combination with durvalumab. The results from a cohort of heavily pretreated prostate cancer patients (median five prior treatments) showed response in a subset of patients and suggest that progression-free survival was prolonged in patients with evidence of higher adenosine-associated gene expression relative to those lacking this signature.
Abstract 5520 – ProCAID: A randomized double-blind Phase II clinical trial of capivasertib in combination with docetaxel and prednisolone chemotherapy in metastatic castration-resistant prostate cancer
Prostate cancers often display aberrant signaling of the PI3K/AKT/mTOR signaling pathway, in part due to the loss of the tumor suppressor PTEN. Preclinical data has suggested possible synergy between inhibition of AKT and docetaxel chemotherapy. In this trial, patients with metastatic castration-resistant prostate cancer were randomized to standard of care docetaxel chemotherapy in combination with the pan-AKT inhibitor capivasertib. The primary endpoint of median progression-free survival was not met in this trial, though this may be because the proportion of patients found to have PTEN-loss by immunohistochemistry (IHC) (~30%) was low. Intriguingly, there was an increase in the secondary endpoint of overall survival with combination capivasertib and docetaxel relative to docetaxel alone. The reasons for this overall survival benefit are not clear and may relate to cohort-specific factors, the complexity of PI3K/AKT signaling in tumor cells and surrounding stroma, or other off-target drug effects as these clinical outcomes were consistent regardless of PTEN status.
Together these trials suggest a framework for ongoing prostate cancer therapeutic development. Improved disease classification from biologic insights can lead to “reverse translation”, where biologically informed therapies are tested within disease subclasses using novel trial designs to overall accelerate the development of treatments that improve patient outcomes.
Presented by: Ana Aparicio, MD, Associate Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, Boston, Massachusetts, at the 2020 American Society of Clinical Oncology Virtual Annual Meeting (#ASCO20), May 29th-May 31st, 2020