April 01, 2014
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Several agents in development may help overcome resistance in advanced prostate cancer

Advanced prostate cancer has undergone a revolution in the past few years, with six new agents approved for castrate-resistant disease.

The putative mechanisms of action for these agents include the androgen receptor pathway, immunotherapy, chemotherapy and bone-targeted therapies.

The increasing understanding of the function of androgens and androgen receptors led to the development of two new oral therapeutic agents.

Daniel P.  Petrylak, MD

Daniel P. Petrylak

Abiraterone acetate (Zytiga, Janssen) is a CYP17 inhibitor. Through this mechanism of action, it blocks the synthesis of androgens in the testes, adrenal glands and prostate tumor tissue. Enzalutamide (Xtandi, Astellas) is an androgen receptor inhibitor that has been shown to competitively inhibit androgen binding to androgen receptors and inhibit androgen receptor nuclear translocation, thus inhibiting androgen receptor binding to DNA.

In phase 3 trials in patients who have progressed after docetaxel chemotherapy, both of these agents significantly improved OS compared with placebo in patients with castration-resistant prostate cancer (CRPC). Additionally, new data presented in September at the European Cancer Congress in Amsterdam showed that co-targeting metastatic CRPC with the combination of enzalutamide plus abiraterone may lead to more profound suppression of androgen signaling than either agent alone.

Other recent groundbreaking advances include:

  • Sipuleucel-T (Provenge, Dendreon), a first-of-its-kind vaccine therapy approved for an advanced solid tumor that was approved for the treatment of asymptomatic or minimally symptomatic metastatic CRPC;
  • Cabazitaxel (Jevtana, Sanofi-Aventis), approved in 2010 as the first second-line chemotherapy to improve survival for men with metastatic CRPC;
  • Denosumab (Xgeva, Amgen), approved for the prevention of skeletal-related events in patients with bone metastases from solid tumors; and
  • Radium Ra 223 dichloride (Xofigo, Bayer), approved for the treatment of CRPC that has spread to bones but not to other organs.

Despite the progress, intrinsic and acquired resistance to each new therapeutic agent continues to be a challenge for oncologists and patients.

Durable complete responses are rarely, if ever, observed. Even in cases when significant responses are seen initially, these agents may activate survival pathways that drive treatment resistance, enabling CRPC to recur and progress.

The identification of new ways to overcome treatment resistance is critically important. Researchers are now working to understand the adaptive tumor responses to therapies that lead to tumor resistance. By identifying these mechanisms and ways to inhibit these processes, it may be possible to extend treatment response and potentially survival.

There are several innovative and promising new agents on the horizon under investigation for the treatment of advanced CRPC:

  • ARN-509 (Aragon) is a second-generation androgen receptor antagonist with a mechanism of action similar to enzalutamide. Trials are underway to evaluate ARN-509 in patients with non-metastatic CRPC, as well as combined with abiraterone in men with metastatic disease.

Preliminary results from the phase 2 portion of a multicenter phase 1/phase 2 trial were presented at the 2013 Genitourinary Cancers Symposium. Those findings suggest ARN-509 is safe, well tolerated and has promising activity in high-risk non-metastatic CRPC. Evaluations of the compound in chemotherapy-naive patients both before and after treatment with abiraterone are ongoing.

  • Custirsen (OncoGenex) is an investigational compound designed to block the production of the protein clusterin, which may play a fundamental role in cancer cell survival and treatment resistance.

Data available from two phase 2 trials in metastatic CRPC suggest the addition of custirsen to first- and second-line chemotherapy has the potential to enhance chemotherapy-induced apoptosis through clusterin inhibition. In the first-line setting, results of a study by Chi and colleagues showed median OS was 23.8 months for patients treated with custirsen plus first-line docetaxel/prednisone compared with 16.9 months for patients treated with docetaxel/prednisone alone.

Results from the first-line phase 3 SYNERGY trial, which evaluated custirsen combined with first-line docetaxel, are anticipated in mid-2014. A second phase 3 trial, AFFINITY, is ongoing to evaluate custirsen combined with cabazitaxel (Jevtana, Sanofi-Aventis) as second-line chemotherapy.

  • Prostvac (Bavarian Nordic), an alternative vaccine strategy to sipuleucel-T, is a therapeutic vaccine that induces a specific, targeted immune response that attacks prostate cancer cells when administered subcutaneously. It is being evaluated in the phase 3 PROSPECT trial in patients with asymptomatic or minimally symptomatic metastatic CRPC. Results are anticipated in 2016. Patients who have metastatic disease and have failed hormone therapy will be eligible to enroll in the trial.

PROSPECT is based on results of a placebo-controlled phase 2 trial conducted by Kantoff and colleagues. At 3-year follow-up, patients assigned to Prostvac had a higher OS rate (30% vs. 17%). Median OS also was longer in the Prostvac arm (25.1 months vs. 16.6 months; P=.0061).

  • Tasquinimod (ABR-215050, Active Biotech) is an oral compound quinoline-3-carboxamide derivative with antiangiogenic and antitumorigenic action that has shown potential combined with other established treatments for advanced prostate cancer, with which resistance has been an issue. A phase 3 clinical trial is currently ongoing to evaluate tasquinimod compared with placebo in patients with asymptomatic to mildly symptomatic metastatic CRPC. Additionally, a phase 1 clinical trial is underway to determine the recommended dose of tasquinimod combined with cabazitaxel and prednisone in men with metastatic CRPC after treatment with docetaxel.
  • Cabozantinib (Cometriq, Exelixis) is a dual tyrosine kinase inhibitor that has shown activity against multiple targets, including RET, MET and VEGFR2, which play a role in both normal cellular function and pathologic processes.

Although other tyrosine kinase and VEGR inhibitors have failed to improve clinical outcomes, results thus far for cabozantinib remain promising.

Smith and colleagues conducted a phase 2 randomized discontinuation trial that included patients with metastatic CRPC. All patients received 100 mg cabozantinib daily. At 12 weeks, those with stable disease were randomly assigned to cabozantinib or placebo. Median PFS was 23.9 weeks in the cabozantinib group vs. 5.9 weeks in the placebo group. Based on the observed activity of cabozantinib, the trial was stopped early.

Enrollment in a COMET-1, a pivotal phase 3 trial designed to evaluate cabozantinib vs. prednisone in patients with CRPC, was completed in September. A second phase 3 trial, COMET-2, will evaluate pain response with the compound vs. mitoxantrone plus prednisone in patients with CRPC. Enrollment is underway.

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Another recently initiated project of note is the Targeting Adaptive Pathways in Metastatic Treatment-Resistant Prostate Cancer Project, which aims to identify the adaptive tumor responses to treatment that lead to tumor resistance. It also will evaluate signaling pathways in prostate cancer — including androgen receptor signaling, and the PI3K and MAPK pathways — that are important in resistance to therapies used to treat advanced disease.

Conclusion

Clinical trial-based research continues to be a vital component of cancer care; however, awareness of opportunities to participate in this type of research is extremely low.

As physicians who strive to provide the best possible care, it is our responsibility to help educate our patients about research-driven care and help them make informed decisions about what option is right for them.

Exciting new possibilities exist as we continue to expand our understanding of these complicated pathways and evaluate these innovative agents in the hopes that we can even further improve survival for patients with castration-resistant disease.

References:

Chi KN. J Clin Oncol. 2010;28:4247-4254.

Efstathiou E. Abstract #2854. Presented at: European Cancer Congress; Sept. 27-Oct. 1, 2013; Amsterdam.

Fizazi K. Lancet Oncol. 2012;13:983-992.

Kantoff PW. J Clin Oncol. 2010;28:1099-1105.

Scher HI. N Engl J Med. 2012;367:1187-1197.

Smith DC. J Clin Oncol. 2013;31:412-419.

Smith MR. Abstract #7. Presented at: Genitourinary Cancers Symposium; Feb. 14-16, 2013; Orlando.

For more information:

Daniel P. Petrylak, MD, is a professor of medicine (medical oncology) and urology, director of the Prostate Cancer Research Group and co-director of the Signal Transduction Program at Yale Cancer Center. He can be reached at Prostate and Urologic Cancer Program, Smilow Cancer Hospital at Yale–New Haven, South Frontage Road and Park Street, 4th floor Multispecialty Care Center, New Haven, CT 06510.

Disclosure: Petrylak reports no relevant financial disclosures.