ABSTRACT: In recent years, management of prostate cancer has benefited from an expanding array of new pharmacological options that are the result, in part, of an increased understanding of, and ability to target, androgen signaling. Further characterization of additional molecular pathways relevant to prostate cancer tumorigenesis has identified new molecular targets in prostate cancer that may be amenable to therapeutic intervention with novel agents. In addition, novel radioisotope therapies and cytotoxic agents have shown significant anticancer efficacy with manageable patterns of toxicity, and will eventually have to be integrated into our algorithms of therapy. This review summarizes recent findings in clinical prostate cancer research reported at the 2012 Annual Scientific Meeting of the American Society of Clinical Oncology (ASCO) and addresses their relevance to clinical practice.
Initial Hormonal Therapy in Metastatic Disease
Inhibition of androgen signaling remains a core treatment strategy in patients with prostate cancer. Although first-line androgen-deprivation therapy (ADT) with luteinizing hormone-releasing hormone analogs (LHRHa) remains standard in patients with metastatic castrate-sensitive disease, the optimal schedule of ADT has been debated. Continuous androgen deprivation (CAD) leads to skeletal and cardiovascular complications as well as to decrements in quality of life due to impaired sexual function. Intermittent androgen deprivation (IAD) in castrate-sensitive patients has been pursued in an attempt to lessen the adverse effects of ADT, although the impact on disease and overall survival (OS) with this approach has not been clearly defined. Randomized trials have suggested IAD has no detrimental impact on OS in this patient population, although these trials have been insufficiently powered to draw firm conclusions.[2-4]
In the early 1990s, the Southwest Oncology Group (SWOG) trial SWOG 9346 (INT-0162) was designed as a randomized phase III study to assess the impact on overall survival of IAD vs CAD in patients with androgen-dependent, metastatic disease. The final results of this trial were reported in a plenary session at the 2012 annual scientific meeting of the American Society of Clinical Oncology (ASCO). Patients with measurable disease and a prostate-specific antigen (PSA) level ≥ 5 ng/mL initially received 7 months of continuous, combined androgen blockade with a LHRH-agonist and an antiandrogen. A total of 3040 patients were accrued to this trial, and 1535 patients achieved a PSA level ≤ 4 ng/mL after the induction phase of CAD. Of this latter group of responding patients, 759 were randomized to remain on continuous androgen deprivation while 770 patients transitioned to IAD. After a median follow-up of 9.2 years, median OS trended towards benefit in the CAD arm following randomization (5.8 vs 5.1 years), but failed to reach statistical significance for the entire study population (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.95 to 1.24). Subset analysis revealed that in patients with extensive disease (defined as involvement of ribs, long bones, and/or visceral organs), IAD was not inferior; however, in patients with minimal disease (defined as involvement of spine, pelvis, and/or lymph nodes), CAD was statistically superior to IAD. In this subset, the median OS times for patients on the CAD and IAD arms were 7.1 and 5.2 years, respectively (HR, 1.23; 95% CI, 1.02 to 1.49, P = .034). The authors concluded that CAD remains preferable to IAD, particularly in patients with minimal disease. Of note, detailed discussion of the patterns of toxicity will form the basis of a future publication from these investigators. The view of the authors regarding superiority of CAD seems to be a very reasonable position, although it is important to note that there was considerable controversy and discussion in a planned session at the 2012 ASCO Annual Meeting. In this session, it was noted that the difference in outcome overall was not very large, and it was suggested that toxicity is significantly less among patients on IAD. Thus an alternative view, which we favor, is that it may be preferable to share the information with patients, particularly those with extensive disease, explaining the amplitude of the difference in survival, accompanied by a discussion of potential toxic effects of CAD and IAD. This would allow each patient to make an informed decision predicated on the balance between efficacy and survival vs the toxicity of treatment, allowing patients to choose a treatment that best reflects their own imperatives and concerns.
Salvage Hormonal Therapy
In the castrate-resistant setting, recent clinical progress has been achieved by therapeutic targeting of extragonadal androgen synthesis and more potent inhibition of androgen-receptor signaling. The enzyme CYP17 is responsible for androgen production in the adrenal glands. Weak inhibition of this enzyme by ketoconazole(Drug information on ketoconazole) demonstrates modest activity in patients with castrate-resistant disease, which sometimes may be sustained for many months.
Abiraterone acetate (Zytiga), developed as a more potent inhibitor of CYP17, reduces systemic androgens to undetectable levels when used in combination with an LHRHa. Complete ablation of systemic androgens in the castrate setting has proven beneficial, as shown by a 3.9-month OS benefit for treatment with abiraterone and prednisone(Drug information on prednisone) compared with prednisone alone in patients previously treated with docetaxel(Drug information on docetaxel) (Taxotere) (Table). Currently, docetaxel is the only agent approved for initial use in patients with mCRPC; however, use of docetaxel in this setting is often limited by declining patient fitness or preference, as well as by occasional patterns of excessive toxicity vs clinical benefit, thus there is much interest in developing more effective second-line hormonal therapies in the chemonaive setting.
An early-phase trial of abiraterone in the chemonaive setting demonstrated antitumor activity, prompting design of the COU-AA-302 trial, which is a multinational randomized phase III study evaluating the efficacy of abiraterone in mCRPC patients prior to their receiving docetaxel-based therapy. A total of 1088 patients with minimal or no symptoms were randomized to receive abiraterone with prednisone vs placebo with prednisone. Following a preplanned interim analysis of results after a median follow-up of 22.2 months, the study was unblinded as recommended by the data monitoring committee after abiraterone demonstrated benefit in all endpoints. OS favored abiraterone over placebo (not reached [NR] vs 27.2 months, respectively: HR, 0.75; 95% CI, 0.61 to 0.93; P = .0097), and the co-primary endpoint of radiographic progression-free survival (rPFS) also showed significant benefit of abiraterone over placebo (NR vs 8.3 months, respectively: HR, 0.43; 95% CI, 0.35 to 0.52; P < .0001). The overall response rate (ORR) of the abiraterone cohort was 36% vs 16% in the placebo arm (P < .0001), a particularly important point that illustrates the innate heterogeneity of clinical progression of this disease. Furthermore, time to initiation of chemotherapy was delayed by 8.4 months in the group receiving abiraterone. These results potentially support a role for abiraterone in the chemonaive setting, although regulatory approval for this indication has not yet been granted.
Additional targeting of the androgen axis has resulted from development of more potent androgen receptor (AR) antagonists. Enzalutamide (Xtandi) binds ARs with higher affinity than bicalutamide(Drug information on bicalutamide) (Casodex), leading to greater inhibition of AR signaling. Based on promising early-phase studies, the AFFIRM trial randomized 1199 men with mCRPC previously treated with docetaxel 2:1 to receive enzalutamide vs placebo. Following preplanned interim analysis, the study was unblinded early due to a marked benefit in the enzalutamide arm. On the basis of superior median OS favoring enzalutamide (18.4 months vs 13.6 months; HR, 0.631; 95% CI, 0.529 to 0.752; P < .001), the United States Food and Drug Administration (FDA) approved enzalutamide for use in docetaxel-treated men with mCRPC on August 31, 2012. The rPFS was significantly prolonged in the enzalutamide arm (8.3 vs 2.9 months; HR, 0.404; 95% CI, .350 to .466; P < .0001), and the ORR was 28.9% vs 3.9% in the placebo arm. Like abiraterone, enzalutamide is also anticipated to have activity in the pre-docetaxel setting, although this question is the subject of the ongoing PREVAIL trial (National Cancer Institute [NCI] Clinical Trials.gov identifier: NCT01212991).
The success of abiraterone and enzalutamide have renewed our interest in targeting androgen signaling in mCRPC. With these new agents, clinicians are challenged with how best to use them in practice to optimize patient outcomes. Little is known about the efficacy of these agents when used in sequence, and whether synergism may exist when they are used in combination or with traditional cytotoxic agents. Because abiraterone and enzalutamide disrupt androgen signaling through different mechanisms, cross-resistance may not be universal. This is suggested by the findings from a small retrospective series of 24 patients with mCRPC treated with abiraterone who had progressed following treatment with docetaxel and enzalutamide. In this series, 13% of patients experienced a PSA decline of > 50%, and 29% experienced a reduction in pain and decreased analgesic use, suggesting a modest benefit to sequential use of these new agents. We believe that a more promising approach will be the use of these agents in combination, which is the focus of an ongoing phase II study (NCT01650194).
The landscape of treatment options for advanced prostate cancer is evolving quickly following recent approval of multiple new agents. Defining how best to use these agents is the subject of many ongoing clinical trials and will likely be an area of active clinical research for many years. Furthermore, development of additional compounds targeting androgen signaling continues, including AR antagonist ARN-509, which has demonstrated encouraging activity in a phase I trial and is currently being evaluated in the phase II setting (NCT01171898). Orteronel (TAK-700) is a novel CYP17 inhibitor, similar to abiraterone, that has also demonstrated encouraging early-phase activity and is also being evaluated in the phase III setting (NCT01193257, NCT01193244).
Hormonal Therapy in Nonmetastatic Disease
Docetaxel improves survival in patients with mCRPC, although it is unknown whether adjuvant chemotherapy is beneficial to high-risk patients following prostatectomy. The TAX-3501 trial, which randomized high-risk patients to immediate or delayed docetaxel following prostatectomy, closed prematurely due to poor accrual. This reflects waning enthusiasm from patients and physicians alike for the use of traditional cytotoxic agents in the perioperative setting given the increasing availability of more effective options for hormonal therapy, and also the demonstration of unexpected toxicity from adjuvant mitoxantrone(Drug information on mitoxantrone) in the SWOG 9921 trial.
In the neoadjuvant setting, ADT has not shown conclusive benefit to date, which may be due in part to persistent intraprostastic androgens, or perhaps is a function of relatively short durations of induction therapy or heterogeneity of receptor expression in many cases. Since the combination of abiraterone and LHRHa can achieve undetectable systemic androgen levels, the impact on intraprostatic androgen levels is also being investigated.[21,22] Taplin et al reported preliminary findings of a phase II neoadjuvant study assessing the use of preoperative abiraterone and LHRHa. All 58 patients received preoperative LHRHa therapy for 24 weeks and concurrent abiraterone during the second 12 weeks prior to radical prostatectomy; 30 of the 58 patients also received concurrent abiraterone during the entire 24-week preoperative period. All patients underwent re-biopsy after 12 weeks for measurement of the impact on intraprostatic androgens, which has not yet been reported. In the initial report, 1 patient (4%) in the LHRHa-only arm achieved a PSA nadir ≤ 0.2 ng/dL compared with 26 patients (90%) in the group receiving both LHRHa and abiraterone after the first 12 weeks of neoadjuvant hormonal therapy. Interestingly, this difference was overcome during the final 12 weeks of preoperative therapy following the addition of abiraterone to the cohort that received only LHRHa therapy initially. The proportion of patients achieving a PSA nadir ≤ 0.2 ng/dL was similar in both groups after 24 weeks total (85% vs 86%). Despite the PSA response, the duration of maximal androgen blockade may be more important to clinical outcome, as the group receiving abiraterone for the entire 24-week preoperative period attained a 34% total or near complete response (CR) rate compared with 15% in the group who received abiraterone only for the final 12-week period (P = .0894).
Preliminary results were also reported by Efstathiou et al for a similar study of neoadjuvant abiraterone and LHRHa. In this randomized phase II trial, patients with high-risk local prostate cancer were randomized 2:1 to receive neoadjuvant abiraterone and LHRHa vs LHRHa alone for 12 weeks before prostatectomy. Primary endpoints include pathologic down-staging and safety. Interim analysis of 37 patients demonstrated that the group receiving both agents had a greater likelihood of undetectable preoperative PSA (68% vs 0%, P = .0001), a surprising result in our experience and the reports of others. Near complete cytoreduction, defined as < 6 mm of scattered cells, also favored patients receiving both agents (24% vs 8%), and pT2N0 pathologic staging occurred in more patients treated with both agents (60% vs 33%, P = .17). A similar phase II neoadjuvant trial is planned with enzalutamide (NCT01547299). These findings suggest neoadjuvant abiraterone may enhance the tumoricidal effect of LHRHa therapy, although whether this will translate into meaningful clinical benefit remains to be seen and will likely require longer durations of perioperative hormonal therapy.
At present, these approaches must be viewed as investigational until there is Level 1 evidence to show that neoadjuvant hormonal therapies, either with conventional approaches or incorporating some of the novel agents and regimens reported at ASCO, improve OS. At the Levine Cancer Institute, our standard off-protocol is to stage patients with high-risk disease carefully, and to use regimens supported by Level 1 evidence for patients with newly diagnosed prostate cancer, focusing either on combined modality hormones and radiation or on radical prostatectomy with adjuvant hormonal therapy for patients with local spread.