The rationale for the intensification of androgen receptor signaling inhibition is that persistent androgen receptor signaling is an important growth mechanism in both castration-sensitive and castration-resistant prostate cancer (CRPC). Furthermore, there is a potential benefit from the suppression of persistent androgen receptor activity suggested by the presence of residual androgens and androgen receptor signaling in hormone-naïve prostate tissue and CRPC metastases after standard androgen deprivation. For metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-resistant prostate cancer (nmCRPC), and metastatic castration-resistant prostate cancer (mCRPC), it has clearly been shown that ADT alone is too little ADT: each setting has demonstrated over several trials that there is an overall survival benefit from inhibiting residual androgen receptor signaling unequivocally demonstrated by the addition of a single agent second-generation androgen receptor signaling inhibitor to standard ADT. In the nonmetastatic castration-sensitive prostate cancer (nmCSPC) (neoadjuvant) setting, the benefit of androgen receptor treatment intensification is still pending. The addition of single-agent androgen receptor signaling inhibitors to ADT has been associated with no improvements in historical rates of pathological complete response. However, small studies show modest but consistent improvements in minimal residual disease, potentially associated with improvements in prostate-specific antigen (PSA) relapse. In neoadjuvant studies of androgen receptor treatment intensification, improvements in post-treatment pathological findings appear to be associated with PSA recurrence, however, validation of pathologic response as a surrogate for metastasis-free survival is currently being assessed in the Phase III PROTEUS study.
Additionally, there is a rationale for dual androgen receptor signaling inhibition. From the moment second-generation agents targeting ligand synthesis versus the androgen receptor became available, the hypothesis arose that dual androgen receptor pathway inhibition should improve outcomes. Pre-clinical and correlative data in CRPC show treatment with second-generation ligand synthesis or androgen receptor inhibitors is associated with reciprocal induction of androgen receptor expression or ligand synthesis. So, can dual androgen receptor signaling intensification prevent or delay resistance in the mCRPC setting? Furthermore, in the neoadjuvant setting, the addition of single-agent androgen receptor signaling intensification to ADT is associated with evidence of continued androgen receptor pathway activation. So, can dual androgen receptor signaling intensification improve the trend toward improved minimal residual disease? Dr. Mostaghel notes that in the Alliance A031201 trial, the median OS with dual androgen receptor signaling intensification versus enzalutamide was similar to pre-chemo studies of abiraterone (Cougar 302: 34.7 vs 30.3 months) and enzalutamide (PREVAIL: 35.3 vs 31.3 months). As such, there is no apparent benefit of dual androgen receptor signaling intensification in mCRPC, but can dual androgen receptor signaling intensification optimize response to CSPC even if not in mCRPC? Dr. Mostaghel notes that ligand suppression appears required for optimal PSA response in mCSPC in that substitution of CYP17A inhibitor versus LHRH agonist is likely to be associated with increased symptomatic events and drug interactions. However, evaluating single-agent abiraterone versus LHRH agonists may be of interest in men with high adrenal androgens where testicular suppression alone may be inadequate. Whether there is a role for single-agent androgen receptor antagonist therapy in mCSPC is debatable. There may be an acceptable strategy in a subset of patients who refuse androgen suppression, whereby the long-term benefit may be adequate in patients with low-volume/low-risk disease. For patients with nmCSPC, looking across several studies, there is no real difference in 10% pCR rates of 15-25% pCR+minimal residual disease observed in neoadjuvant studies of single-agent androgen receptor signaling intensification + ADT.
To summarize dual androgen receptor signaling intensification in prostate cancer, Dr. Mostaghel highlights that there is an apparent ceiling on pathologic improvement achieved by single or dual androgen receptor signaling intensification inhibition in the neoadjuvant setting. Response to the primary tumor may or may not be a surrogate for controlling micrometastatic disease, which is where the Phase III PROTEUS study will be informative in this regard. He notes that it is worth mentioning that prostate tumor cells in situ may be more robust to androgen receptor suppression than disseminated cells in a less supportive microenvironment, whereby the lack of response in the primary may not portend a lack of systemic effect.
The bottom line according to Dr. Mostaghel is that there is no apparent benefit of adding dual versus single-agent second-generation androgen receptor signaling intensification in castration-resistant or castration-sensitive settings. Dual androgen receptor signaling inhibition is likely to enhance the induction of androgen receptor splice variants lacking the androgen receptor binding domain, which may counter added benefits of combining agents that all target the androgen receptor ligand-binding domain. Even if androgen receptor splice variants are an epiphenomenon of increased full-length androgen receptor expression (due to amplification or overexpression), the increased androgen receptor needs to be targeted. This suggests that to fully test the hypothesis of maximal androgen receptor signaling inhibition, we need agents with activity against androgen receptor splice variants such as N-terminal inhibitors, or androgen receptors degraders, if blocking the androgen receptor-ligand binding and/or DNA translocation is not sufficient.
Whether we can identify patients in whom intense ADT is just right is likely associated with the identification of pre-treatment biomarkers associated with androgen receptor signaling responsive or resistant phenotype. Correlative work presented at the 2020 ASCO Virtual Annual Meeting by Efstathiou et al. and McKay et al. suggests that (i) absence of nARV7, GR low Ki67 less than 10% is associated with a therapeutic effect, and (ii) SPOP is associated with a response, as well as PTEN loss/TMPRSS2-ERG fusions associated with resistance.
Dr. Mostaghel concluded her presentation with several key take-home points:
- Of particular importance are pre-treatment biomarkers associated with an androgen receptor signaling responsive or resistant phenotype
- Correlative work in the neoadjuvant studies is a key step in addressing the question of correctly identifying who benefits from intense ADT
- The androgen environment may be a key dictator of response to androgen receptor inhibition in that there exists a subset of patients with a more robust adrenal axis that is incompletely abrogated by single androgen receptor path inhibition, and this may be the population most likely to benefit from dual androgen receptor signaling intensification
- However, tumors selected in lower androgen environment may be more likely to harbor androgen receptor-independent aberrations and may be less likely to benefit from dual androgen receptor inhibition
Presented by: Elahe A. Mostaghel, MD, PhD, Associate Professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, The University of Washington, Seattle, Washington
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, Twitter: @zklaassen_md, at the 2020 American Society of Clinical Oncology Virtual Annual Meeting (#ASCO20), May 29th-May 31st, 2020