	Assistant Professor, Department of Hematology and Medical Oncology

Although the incidence and mortality of prostate cancer remain formidable problems in the United States, clinicians have many new agents with proven overall survival (OS) benefits to recommend for patients with metastatic disease. Now, these agents are being studied intensely in earlier settings with notable success.

This progress makes for exciting times in the battle against prostate cancer, which is projected to result in 233,000 newly diagnosed cases and 29,480 deaths in the United States in 2014.

 Yet these advancements also present a new set of challenges for physicians who treat men with this malignancy.

As research findings unfold, oncologists will have to help balance the benefits of these agents with practical challenges such as cost and safety. As clinicians, we also must be available to help patients and colleagues navigate these considerations in an increasingly complex treatment paradigm.

During the past decade, six agents with varying mechanisms of action have demonstrated OS benefits for patients with metastatic castration-resistance prostate cancer (mCRPC). These agents include abiraterone acetate and enzalutamide, which target the androgen axis; docetaxel and cabazitaxel, which are both taxanes; sipuleucel-T, an autologous therapeutic cancer vaccine; and radium-223, a bone-targeted alpha emitter (

		Table 1. Agents With Overall Survival Benefit in mCRPC

		BSC indicates best standard of care; HR, hazard ratio; mCRPC, metastatic castration-resistant prostate cancer.

Several of these agents have demonstrated efficacy in earlier settings after large comparative clinical trials(

Data Supporting Earlier Use of Approved Therapies 

Recent data from the 2014 American Society of Clinical Oncology Annual Meeting constitute groundbreaking progress in hormone-sensitive prostate cancer.

The ECOG 3805 CHAARTED study examined the use of docetaxel and androgen deprivation therapy (ADT) versus ADT alone for patients with hormone-sensitive metastatic prostate cancer.

Those in the docetaxel arm received standard dosing at 75 mg/m² every 21 days times 6 cycles with a primary endpoint of OS. The trial accrued 790 men. At the planned interim analysis, there was a statistically significant OS benefit with median survival of 44 months with ADT alone versus 57.6 months with ADT plus docetaxel. In men with high-volume disease (visceral or extensive bone metastases), patients who received ADT plus docetaxel had a median OS of 49.2 months, whereas those receiving ADT alone had a median OS of 32.2 months. This 17-month difference in median OS early in the disease process by far exceeds recent gains with new prostate cancer agents in mCRPC. This landmark study is the latest in the significant trend in testing proven therapies in earlier stages of prostate cancer.

Studies in metastatic prostate cancer also illustrate this growing trend. Abiraterone is now used in the chemotherapy-naïve mCRPC setting based on outcomes among patients who already have received docetaxel therapy. In the COU—AA–302 trial, men who were chemotherapy naïve were randomized to receive abiraterone and prednisone versus placebo and prednisone. There was a statistically significant difference in OS, measured at 27.2 months in the prednisone-alone group as compared with median OS that had not yet been reached in the abiraterone arm.

 There also was an increase of progression-free survival (PFS) from 8.3 months to 16.5 months, respectively, between the standard and the abiraterone groups.

		Table 2. Studies Support Earlier Indications in Prostate Cancer

					Abiraterone/prednisone vs placebo/prednisone

					Newly diagnosed, hormone sensitive mPC

					OS: 57.6 vs 44.0; high volume tumors OS: 49.2 vs 32.2

		CRPC indicates castration-resistant prostate cancer; HR, hazard ratio; mPC, metastatic prostate cancer; NR, not reached; OS, overall survival; PFS, progression-free survival.

Similarly, enzalutamide has been studied in the mCRPC chemotherapy-naïve population. The recently published PREVAIL study was a randomized placebo-controlled phase III trial of enzalutamide in such patients.

 After interim analysis, the trial was stopped early due to the dramatic reduction in events of patients who received the agent. There was a 65% radiographic PFS of 12 months among patients treated with enzalutamide versus 14% among patients who received placebo.

The hazard ratio for this difference was 0.19 and was highly statistically significant. An updated analysis showed the estimated median OS was not yet reached in the enzalutamide arm compared with 31.0 months in the placebo group. There was a 29% decrease in the risk of death among those patients who received enzalutamide. In mid-September, the FDA approved this agent in the prechemotherapy setting.

Many Challenges in Shifting Treatment Timelines 

The use of approved agents in earlier settings of both hormone-sensitive disease and mCRPC benefits patients but also presents challenges. The novel findings from the CHAARTED study beg the question of whether other agents that are approved or being studied in CRPC could show similar benefits in the hormone-sensitive setting as well.

For example, cabazitaxel is already being tested against docetaxel as frontline chemotherapy in men with mCRPC.

 It is interesting to hypothesize about whether cabazitaxel could also lead to an even greater OS benefit in the hormone-sensitive setting when combined with ADT.

A second problem with multiple successful novel agents for prostate cancer concerns the sequencing of these drugs in early settings in order to optimize effect. For example, docetaxel is known to inhibit translocation of the androgen receptor and can affect efficacy with later therapies directed at the androgen axis.

 It has been observed that prior administration of CYP17 inhibitors such as ketoconazole can affect response to both chemotherapy

 and future androgen-targeted agents. Clearly, additional trials are necessary to elucidate optimal sequencing with recently approved agents.

Combinations for the various agents will be important to investigate as well, both in hormone-sensitive disease and in mCRPC. Multiple studies have combined docetaxel with novel agents in mCRPC, but all have failed to show notable OS advantages. Due to the specific mechanisms of some of the AR signaling drugs and the recent success in the early mCRPC setting, combinations of these agents have been examined and will become more important in the early setting as well. For example, enzalutamide in combination with abiraterone in bone mCRPC has been examined in a phase II study.

Patients were able to tolerate the drugs safely, and more than 75% of the participants were noted to have undetectable serum testosterone levels after 8 weeks. The experience with this combination therapy suggests that more efficacious inhibition of the androgen signaling axis is possible and calls for more combination trials of agents that focus on the androgen receptor axis both in hormone-sensitive disease and all stages of CRPC.

The complexity and challenges of earlier use of these agents are increased when one considers the various novel agents under development. Immunotherapy will undoubtedly become more integrated into prostate cancer therapies. For example, a phase II study looking at sipuleucel-T in combination with enzalutamide versus sipuleucel- T followed by enzalutamide is currently under way.

 Similar combinatorial studies are taking place with radiopharmaceuticals. A phase III study examining radium-223 plus abiraterone in patients with chemotherapy-naïve mCRPC is currently enrolling; the Winship Cancer Institute is among the sites seeking to recruit patients for this trial.

These types of trials will undoubtedly promote more studies in both the hormone-sensitive and nonmetastatic CRPC states

			Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014 [published online January 7, 2014]. 

			Sweeney C, Chen Y-H, Carducci MA, et al. Impact on OS with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer: an ECOG-led phase III randomized trial. Presented at: the 50th Annual Meeting of the American Society of Clinical Oncology; May 30-June 2, 2014; Chicago, Illinois. Abstract LBA2.

			Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy [published online December 10, 2012]. 

			Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy [published online June 1, 2014]. 

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT01308567.

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT 01718353.

			Loriot Y, Bianchini D, Ileana E, et al. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100) [published online April 10, 2013]. 

			Schrader AJ, Boegemann M, Ohlmann CH, et al. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone [published online July 2, 2013]. 

			Pond GR, Armstrong AJ, Galsky MD, et al. Efficacy of docetaxel-based chemotherapy following ketoconazole in metastatic castration-resistant prostate cancer: implications for prior therapy in clinical trials [published online May 1, 2012]. 

			Efstathiou E, Titus MA, Wen S, et al. Enzalutamide (ENZA) in combination with abiraterone acetate (AA) in bone metastatic castration resistant prostate cancer (mCRPC). 

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT01981122.

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02043678.

Articles

Although the incidence and mortality of prostate cancer remain formidable problems in the United States, clinicians have many new agents with proven overall survival (OS) benefits to recommend for patients with metastatic disease. 

Bradley C. Carthon, MD, PhD

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