Novel Combinations Hold Promise in Treatment-Resistant mCRPC

Thomas E. Keane, MBBCh

Although the antiandrogen therapies (ADTs) enzalutamide (Xtandi) and abiraterone (Zytiga) demonstrate impressive clinical activity in patients with metastatic castration-resistant prostate cancer (mCRPC), innate or acquired resistance invariably arises, and understanding what’s behind that resistance is a focus of ongoing research.

Agents such as sipuleucel-T, radium 223, and denosumab, used in combination with current therapies, may be on the horizon and are treatment options that the urologist can explore, said Thomas E. Keane, MD, ChB, during his presentation at the 2015 Large Urology Group Practice Association (LUGPA) Annual Meeting.

The existing treatment paradigm for prostate cancer is in flux because of resistance, said Keane. Specifically, the addition of docetaxel caused a paradigm shift and, “everything we thought we understood about this disease changed.

“We thought patients with advanced disease could be treated with Xtandi and Zytiga postchemotherapy. Then we discovered those agents could be given prechemotherapy. Now, we have learned that chemotherapy can be given before everything, and the order of sequencing—for agents such as Xgeva, Yervoy, Xofigo, Jetvana—is yet to be determined. All of these agents will eventually find their place.”

A Plethora of Studies

The phase III COU-AA-302 trial evaluated the use of abiraterone in individuals with CRPC who had not received chemotherapy. Median survival for men treated with abiraterone was approximately 35 months, compared with 30 months for patients who initially received prednisone and placebo (P = .0033). The phase III PREVAIL trial confirmed the survival benefit of enzalutamide over placebo with an updated overall survival (OS) analysis demonstrating a 23% reduction in the risk of death and a 4-month improvement in median survival with enzalutamide.But once resistance develops in the patient given ADT, what are the next steps?

“We need to remember that prior to COU-AA-302 and PREVAIL, two-thirds of mCRPC patients saw an oncologist and two-thirds of those patients received docetaxel,” said Keane. “So, about 45% of patients were not receiving life-prolonging therapy after ADT failure. The clinical trials STAMPEDE and CHAARTED may be changing this.”

The landmark CHAARTED trial investigated the impact of chemotherapy with ADT on the treatment of patients with hormone-naïve, metastatic prostate cancer. The combination resulted in a median OS of 57.6 months compared with 44 months in the ADT-alone arm (HR, 0.61; P = .0003).

“This study was a game-changer; this took everybody by surprise,” said Keane.

STAMPEDE is the largest randomized prostate cancer trial ever conducted, and was presented at the 2015 ASCO Annual Meeting. In this study, researchers reported that adding docetaxel to standard hormonal therapy significantly improved survival among men with newly diagnosed hormone-naïve advanced prostate cancer.

For patients who develop resistance on docetaxel therapy, second-generation taxanes like cabazitaxel may offer another option, as demonstrated by the phase III TROPIC trial. In that trial, median OS was 15.1 months in patients administered cabazitaxel, compared with 12.7 months for patients given mitoxantrone (HR, 0.70; CI 0.59-0.83). Median progression-free survival was 2.8 months in patients treated with cabazitaxel versus 1.4 months in patients treated with mitoxantrone.

IMPACT was the pivotal trial leading to the FDA approval of sipuleucel-T in patients with asymptomatic or minimally symptomatic mCRPC. IMPACT randomized 512 men with asymptomatic or minimally symptomatic mCRPC in a 2:1 ratio to treatment with sipuleucel-T versus placebo. Sipuleucel-T was associated with a significant improvement in OS compared with controls.

Another treatment option to consider when ADT resistance occurs is radium-223, said Keane. This first-in-class, alpha-emitting radiopharmaceutical significantly improved OS, prolonged time to first symptomatic skeletal events, and was safe and well tolerated as demonstrated in the ALSYMPCA phase III trial.

Concomitant medication with radium-223 also shows promise, said Keane. A phase I clinical trial evaluating radium-223 and docetaxel in patients with CRPC and bone metastases established the safety of the combination, leading to the expanded phase IIa safety cohort study. Preliminary findings show that the combination is safe and well tolerated.

Denosumab, a monoclonal antibody, was investigated in a phase III trial reported by Smith et al (Ann Oncol. 2015;26(2):368-374) that compared the antibody’s time to first skeletal related event with zoledronic acid in mCRPC. In that study, denosumab significantly reduced the risk of developing a first symptomatic skeletal event (HR, 0.78; P = .005).

Keane highlighted those trials that are determining how to best sequence and combine second-generation hormonal therapy including: ENZAMET, a phase I trial of niclosamide plus enzalutamide in androgen receptor (AR) splice variant—positive mCRPC (NCT02532114); a phase III trial of ADT plus bicalutamide versus ADT with TAK-700 (a 17,20 lyase inhibitor [NCT01809691]); a phase II trial of AZD5363 plus enzalutamide in patients with mCRPC (NCT02525068), and an open-label study of supraphysiologic testosterone followed by abiraterone or enzalutamide in men with mCRPC who have previously progressed (NCT02090114).

Among docetaxel combination studies, Keane cited a phase Ib safety and dose escalation study in development of the hedgehog inhibitor LDE225 plus docetaxel/prednisone (NCT02182622); a phase I/II trial of looking at cabozantinib plus docetaxel/prednisone in advanced prostate cancer (NCT01683994); and a multicenter study involving enzalutamide retreatment in mCRPC as first treatment post-docetaxel in men who have progressed on enzalutamide in the prechemotherapy setting.

Mechanisms of Resistance

Radium-223 trials of note include a phase II study of radium-223 plus abiraterone or enzalutamide in mCRPC and a phase II study of sipuleucel-T with or without radium-223.Keane also provided an overview of the mechanisms that lead to resistance. “There are six theories of resistance that involve the androgen receptor: the hypersensitive pathway, the outlaw pathway, the promiscuous pathway, coactivation and corepressors, and the bypass pathway.”

In the hypersensitive pathway, the AR becomes extremely sensitive to very low amounts of androgens and results in over amplification of gene products. In the outlaw pathway, the AR pathway is activated by growth factors and receptor tyrosine kinases. AR is receptive to ligands other than dihydrotestosterone in the promiscuous pathway. In the coactivator/corepressor pathway, coactivators are increased in castration resistant cancers, which enhances the sensitivity of AR to ligands other than androgens, and in the bypass pathway, resistance arises when the AR pathway is circumvented and other pathways are used to stimulate prostate cells to proliferate.

Despite these multiple pathways to resistance, Keane concluded his presentation on a positive note: “Suffice it to say that I think that the future is bright, but we have to look at the toxicity of these drugs, we need to look at how we modify the toxicity, we need to look at the staging of our patient when we enroll them in these trials because it all has changed and every year it seems we have a new area that we need to explore further.”

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