New Oral Androgen Receptor Pathway Agents Are Changing the Way Prostate Cancer Is Treated

The treatment of late-stage prostate cancer is shifting. With the approval of two new oral agents, abiraterone acetate (Zytiga) in April 2011 and enzalutamide (Xtandi) in August 2012, there are now options for men with metastatic prostate cancer who have progressed after chemotherapy treatment with docetaxel where there were none just two years ago. Since its initial approval, abiraterone has also been approved by the FDA for the use of abiraterone in chemotherapy-naïve patients with metastatic prostate cancer. Enzalutamide is also being tested in this patient population; a phase III trial is ongoing.

Next-Generation Androgen Receptor Signaling Agents

The reason for the shift? Research over the past 10 years has shown that metastatic prostate cancer tumors that are resistant to hormonal (androgen)- deprivation therapies still rely on androgen receptor (AR) pathways for growth. “Until this decade, we had assumed that tumors from [surgically or medically castrated patients who stopped responding to hormonal treatments] were no longer reliant on hormones for their growth and progression,” said Joshi J. Alumkal, MD, assistant professor of Medicine at the Oregon Health & Science University in Portland.There are several mechanisms by which prostate tumors hijack androgen signaling to fuel cancer growth. Some castration-resistant prostate cancer (CRPC) tumors are able to make testosterone and androgen precursors. These tumors also amplify ARs on prostate cancer cells or develop mutations in AR genes. The next-generation androgen-targeting therapies, abiraterone and enzalutamide, target these mechanisms.

Joshi J. Alumkal, MD

“Abiraterone and enzalutamide are proof that at least in some patients, male hormones still matter and they are promoting prostate cancer growth. Those are the 50% of patients who respond [to these new agents], at least temporarily, and who may derive an overall survival benefit,” said Alumkal.

The two drugs have different mechanisms of action. Abiraterone works by inhibiting CYP17, an enzyme necessary to make a precursor of testosterone in the testes, adrenal glands, and within the prostate tumor itself. Enzalutamide is a second-generation oral antiandrogen that binds to the androgen receptor, inhibiting the interaction of testosterone to its receptor.

“Enzalutamide is selective—it works particularly well in tumors in which the androgen receptor is overactive, such as through amplification,” said Andrew J. Armstrong, MD, MSc, co-leader of the Genitourinary Oncology Research program at Duke University School of Medicine in Durham, North Carolina.

Andrew J. Armstrong, MD

Other novel hormonal agents in development include orteronel (TAK700), another oral nonsteroidal selective inhibitor of androgen synthesis that targets the same enzyme as abiraterone. The oral drug is being tested in phase III trials in patients with metastatic CRPC both before and after treatment with chemotherapy.

Management of Prostate Cancer in Urology Practices

Another novel oral agent, ODM-201, has the same mechanism of action as enzalutamide, and thus interacts with the AR. The drug has shown high response rates in a phase I/II first-in-human trial presented at this year’s European Society for Medical Oncology (ESMO) Congress.As abiraterone, enzalutamide, and other oral androgen-targeting therapies become the standard of care, it is likely that more urologists will be treating patients with advanced prostate cancer and that these patients will remain in the care of their urologists longer, through the progression of their cancer.

This trend of prostate cancer management within urology practices will likely continue as these newer agents move into the nonmetastatic setting. “As we see the data emerge in the nonmetastatic setting, you may see more urologists consider using these drugs because they appear quite safe,” said Armstrong.

Armstrong emphasized that there are serious side effects of these agents that urologists may not wish to manage, such as heart failure, liver toxicity, muscle fatigue, risk of seizure, and drug interactions with other medications. But with proper training, he believes urologists can manage the toxicities.

“One of the differences between medical oncologists and urologists is that medical oncologists have learned how to recognize and handle side effects of cancer therapies because of their experience in handling chemotherapy side effects,” said Stanley A. Brosman, MD, a urologist in Santa Monica, California. Brosman emphasizes that while easy to administer, the new agents are not without side effects. “It is not just prescribing a pill, but educating a patient of potential side effects and learning how to deal with them.”

Table. Selected Oral Androgen-Affecting Agents for the Treatment

of Late-Stage Prostate Cancer

Drug

Description/ MOA

Status

Results Leading to Approval

Other Trial Results

Ongoing Trials

Zytiga (abiraterone acetate)

Selective inhibitor of androgen biosynthesis by the adrenal glands, testes, and prostate cancer (inhibits CYP17 enzyme, necessary for androgen biosynthesis), dosed in combination with prednisone

Approved April 2011 for metastatic CRPC post-docetaxel with prednisone

Approved December 2012 for metastatic CRPC chemotherapy- naïve patients who have failed ADT

Phase III COUAA- 301 trial: 14.8 months median OS on abiraterone vs 10.9 months on placebo

Phase III COU-AA-302 trial: 16.5 months median rPFS on abiraterone vs 8.3 months in control

N/A

Phase II neoadjuvant abiraterone + leuprolide trial (NCT00924469)

Phase II abiraterone + enzalutamide combo trial (NCT01650194)

Xtandi (MDV3100, enzalutamide)

Androgen receptor signaling inhibitor

Approved August 2012 for metastatic CRPC post-docetaxel

Phase III AFFIRM trial: 5-month longer median OS benefit vs placebo (18.4 months in MDV3100 arm vs 13.6 months for placebo arm)

N/A

Phase III PREVAIL chemotherapy-naïve metastatic CRPC trial (NCT01212991)

Phase II neoadjvuant MDV3100 prior to prostatectomy trial (NCT01547299)

Phase II Hormone-naïve prostate cancer trial (NCT01302041)

Phase II TERRAIN trial vs the antiandrogen bicalutamide in asymptomatic CRPC patients who have progressed on hormone therapy (NCT01288911)

Orteronel (TAK700)

Reversible nonsteroidal inhibitor of androgen synthesis (CYP17 inhibitor)

N/A

N/A

Preliminary phase II activity in nonmetastatic CRPC

Preliminary phase II antitumor activity of 41% to 63% of metastatic CRPC patients with more than 50% decline in PSA in 97 patients

Phase III TAK700 maintenance therapy post-first-line docetaxel in metastatic CRPC (NCT01707966)

Phase III TAK700 in chemotherapy-naïve metastatic CRPC trial (NCT01193244)

Phase III TAK700 in metastatic CRPC post-docetaxel trial (NCT01193257)

Phase III TAK700 + hormone therapy + radiotherapy in high-risk patients (NCT01546987)

ODM-201

Androgen receptor antagonist

N/A

N/A

Preliminary antitumor activity of nearly 90% of patients with more than 50% decline in PSA in 15 patients

Phase I/II metastatic CRPC safety and pharmacokinetics trial (NCT01317641)

ADT indicates androgen-deprivation therapy; CRPC, castration-resistant prostate cancer; MOA, mechanism of action; N/A, not applicable; OS, overall survival;

PFS, progression-free survival; PSA, prostate-specific antigen.

Looking to Prevent Resistance

Despite the improvement in overall survival with both abiraterone and enzalutamide, resistance and disease progression is still inevitable. “These drugs have really not shown cures yet for patients in the metastatic setting—all patients eventually progress, and we need to understand how this occurs,” said Armstrong.

What are the escape mechanisms of tumors exposed to these new androgen receptor pathway agents? “That is the million dollar question,” said Alumkal. “With cancer therapy, anything that doesn’t kill a cancer makes it stronger. Tumor cells that can survive the treatment and evolve have activated bypass mechanisms.”

The entire range of resistance mechanisms to these new agents has not been identified, but research is ongoing. “The side effect of these drugs may be to activate other critical survival pathways to sustain these tumors. But that remains to be proven,” said Alumkal. One pathway that may be important when the AR pathway is inhibited is phosphoinositide 3-kinase (PI3K)/AKT. So far the evidence for this resistance mechanism comes from preclinical research, but the combination of a PI3K inhibitor with enzalutamide may not be far off.

The goal is to find new, rational combinations to prevent resistance— or at least to prolong responses or increase response rates. Another goal is to understand why approximately half of patients with metastatic CRPC do not respond to either abiraterone or enzalutamide.

Combinations and Treating Earlier-Stage Prostate Cancer

Alumkal and colleagues are starting their own effort with funding from a Prostate Cancer Dream Team Award sponsored by the Stand Up to Cancer Foundation, the Prostate Cancer Foundation, and the American Association for Cancer Research, using genomic sequencing to categorize tumors before and during treatment with enzalutamide and at time of progression on enzalutamide to understand the differences between patients who respond and those who do not.“My hope is that, for all of these new and promising hormonal agents, we will develop combinations that will work better,” said Alumkal.

One potential combination is abiraterone plus enzalutamide. A pilot phase I study is in progress, testing whether the two drugs are more potent when given in parallel and to understand the toxicities of the combination.

Another approach to boost overall survival for patients with prostate cancer is to study these new hormonal agents in earlierstage prostate cancer. Because cancer becomes increasingly more complex as it progresses, treating patients in the adjuvant or neoadjuvant setting or in combination with surgery or radiation has the potential to improve cure rates, similar to adjuvant hormonal therapy in breast cancer, according to Armstrong.

“The earlier you use these drugs in the metastatic setting, the more active they appear to be. Perhaps if we use them even earlier in presumed micro-metastatic disease, the absolute survival benefit would be better. Trials should be conducted in these settings to address these critical questions,” said Armstrong.

Armstrong also advocates for a trial to compare abiraterone and enzalutamide. There is currently little evidence for which agent should be used first for metastatic disease that has progressed after chemotherapy; however, such a trial by the US Cooperative groups (ALLIANCE) is being planned.

As new research probes the genomic pathways of resistance and examines optimal combinations, there is no doubt that these next-generation androgen-targeting therapies are changing the way urologists treat patients with late-stage prostate cancer.

Image courtesy of Janssen Biotech, Inc.