BALTIC16: Expert warns of drug resistance in mCRPC patients

Although there are small gains in providing hormone and chemotherapy to metastatic castration-resistant prostate cancer (mCRPC) patient, experts cautioned that the increased use of these new agents may lead to new patterns of resistance.

“With increasing use of novel hormonal therapies, new patterns of resistance will likely evolve,” said Prof. Jan-Erik Damber (SE) who gave an overview lecture on the targeting of the androgen receptor pathway in mCRPC at the 3rd EAU Baltic Meeting which was held over the weekend in Tallinn, Estonia.

Saying that castration-resistance prostate cancer (CRPC) is often indicated by both biochemical and radiological progressions such as consecutive rises in PSA and the appearance of two or more new bone lesions, Damber underscored that symptomatic progression alone must be questioned by doctors.

“Symptomatic progression by itself is not sufficient to diagnose CRPC,” said Damber as he cited the EAU Guidelines. He also examined toxicities related to CRPC treatments such as in the case of docetaxel.

“Until now available treatments have either been associated with significant toxicities (docetaxel) or have had limited efficacy (second/third-line hormone therapy),” he noted.

He examined the current landscape of new agents and the various on-going trials that examine overall survival and progression, among other issues. Abiraterone acetate, for instance, is an oral and selective inhibitor of the enzyme CYP17 which is considered a key enzyme in testosterone biosynthesis. Damber also discussed the COU-AA-301 trial (De Bono et al.), a phase 3, multinational, multicenter randomized, double-blind, placebo-controlled study (174 sites in 13 countries in the US, Europe, Australia and Canada). The trial, looked into the combination of abiraterone and prednisone, and daily placebo combined with prednisone.

The trial’s primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to pre-specified criteria), progression-free survival according to radiologic findings based on pre-specified criteria, and the PSA response rate. The study showed that inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with mCRPC who previously received chemotherapy.

Other drugs, according to Damber, which may have a role in improving survival rates are grouped as androgen biosynthesis inhibitors and androgen receptor signaling inhibitors. Under the former are agents such as orteronel (TAK-700), ASP-9521, VT-464 and CFG-920. Signaling inhibitors agents include enzalutamide (MD-3100), ARN-509, ODM-201, AZD-3514 and EZN-4176.

“Improved understanding of the androgen-signaling axis has led to the recent development of novel agents that maintain therapeutic activity despite initial failure of castration, as shown by positive phase 3 trials of arbiraterone and enzaltumide,” said Damber in his concluding remarks.

He also said that the optimal combination, sequence and use of these novel therapies in daily clinical practice will be the focus of clinical research in the future.

“Metastatic CRPC has a heterogenous characteristic,” said Damber as he noted that a “metastatic disease” is actually a “group of diseases even within the same patient.” This pose a challenge to doctors, Damber said, as he emphasised that more studies are needed to shed insights into the impact of these agents in disease progression and the patient's quality of life.