Titration of Androgen Signaling: How Basic Studies Have Informed Clinical Trials Using High-Dose Testosterone Therapy in Castrate-Resistant Prostate Cancer

Since the Nobel Prize-winning work of Huggins, androgen ablation has been a mainstay for treatment of recurrent prostate cancer. While initially effective for most patients, prostate cancers inevitably develop the ability to survive, grow, and metastasize further, despite ongoing androgen suppression. Here, we briefly review key preclinical studies over decades and include illustrative examples from our own laboratories that suggest prostate cancer cells titrate androgen signaling to optimize growth. Such laboratory-based studies argue that adaptations that allow growth in a low-androgen environment render prostate cancer sensitive to restoration of androgens, especially at supraphysiologic doses. Based on preclinical data as well as clinical observations, trials employing high-dose testosterone (HDT) therapy have now been conducted. These trials suggest a clinical benefit in cancer response and quality of life in a subset of castration-resistant prostate cancer patients. Laboratory studies also suggest that HDT may yet be optimized further to improve efficacy or durability of response. However, laboratory observations suggest that the cancer will inevitably adapt to HDT, and, as with prior androgen deprivation, disease progression follows. Nonetheless, the adaptations made to render tumors resistant to hormonal manipulations may reveal vulnerabilities that can be exploited to prolong survival and provide other clinical benefits.

Response to Androgens and Androgen Receptor Antagonists in the Presence of Cytokines in Prostate Cancer

Non-steroidal anti-androgens have a major role in the treatment of non-localized prostate cancer. Interleukins are involved in the regulation of many cellular functions in prostate cancer and also modify cellular response to anti-androgens. A specific role of selected IL is presented in this review. IL-8 is a cytokine expressed in prostate cancer tissue and microenvironment and promotes proliferation and androgen receptor-mediated transcription. In contrast, IL-1 displays negative effects on expression of androgen receptor and its target genes. A subgroup of prostate cancers show neuroendocrine differentiation, which may be in part stimulated by androgen ablation. A similar effect was observed after treatment of cells with IL-10. Another cytokine which is implicated in regulation of androgenic response is IL-23, secreted by myeloid cells. Most studies on androgens and IL were carried out with IL-6, which acts through the signal transducer and activator of the transcription (STAT) factor pathway. IL-6 is implicated in resistance to enzalutamide. Activation of the STAT-3 pathway is associated with increased cellular stemness. IL-6 activation of the androgen receptor in some prostate cancers is associated with increased growth in vitro and in vivo. Molecules such as galiellalactone or niclosamide have an inhibitory effect on both androgen receptor and STAT-3 pathways.

Celebrating the 80th anniversary of hormone ablation for prostate cancer

In this special issue of Endocrine-Related Cancer, we are celebrating the 80th anniversary of hormone ablation as treatment for metastatic prostate cancer. Our understanding has evolved from the observation that androgen withdrawal, either surgical or pharmacological, resulted in prostatic atrophy in animal models, to its application in patients, to investigation of the mysterious way in which prostate cancer escapes androgen dependence. We are now in an era of novel AR pathway inhibitors, combination of androgen ablation with chemotherapy, PARP inhibitors, immunotherapies, guided radiotherapy, and novel drug application based upon genetic testing of individual tumors. In this Anniversary Issue, we bring together a collection of eight reviews that cover not only the history of 80 years of progress after the initial identification of androgen ablation as an effective treatment of prostate cancer, but subsequent improvements in the understanding of the biology of the disease, development of novel treatment paradigms, resistance to those treatments and disease progression following that resistance.

Targeting androgen receptor signaling: a historical perspective

The first case of prostate cancer was identified by histological examination by J. Adams, a surgeon at The London Hospital, in 1853. In his report, Adams noted that the condition was “a very rare disease”. Now, over 150 years later, with increased life expectancy and screening, prostate cancer has become one of the most common cancers in men. In the United Sates alone, nearly 200,000 men are diagnosed with prostate cancer annually and about 33,000 succumb to their disease. Fifty years ago, men were typically diagnosed with prostate cancer in their seventies with disease that had metastasized to the bone and/or soft tissue. Diagnosis at such an advanced stage was a death sentence, with patients dying within two years. The pioneering work of Charles Huggins in the 1940s found that metastatic prostate cancer responds to androgen deprivation therapy (ADT), ushering in the rational use of hormone therapies that have irrevocably changed the course of prostate cancer disease management. Medical castration was the first effective systemic targeted therapy for any cancer and, to this day, androgen ablation remains the mainstay of prostate cancer therapy.

Signaling Pathways That Control Apoptosis in Prostate Cancer

Prostate cancer is the second most common malignancy and the fifth leading cancer-caused death in men worldwide. Therapies that target the androgen receptor axis induce apoptosis in normal prostates and provide temporary relief for advanced disease, yet prostate cancer that acquired androgen independence (so called castration-resistant prostate cancer, CRPC) invariably progresses to lethal disease. There is accumulating evidence that androgen receptor signaling do not regulate apoptosis and proliferation in prostate epithelial cells in a cell-autonomous fashion. Instead, androgen receptor activation in stroma compartments induces expression of unknown paracrine factors that maintain homeostasis of the prostate epithelium. This paradigm calls for new studies to identify paracrine factors and signaling pathways that control the survival of normal epithelial cells and to determine which apoptosis regulatory molecules are targeted by these pathways. This review summarizes the recent progress in understanding the mechanism of apoptosis induced by androgen ablation in prostate epithelial cells with emphasis on the roles of BCL-2 family proteins and “druggable” signaling pathways that control these proteins. A summary of the clinical trials of inhibitors of anti-apoptotic signaling pathways is also provided. Evidently, better knowledge of the apoptosis regulation in prostate epithelial cells is needed to understand mechanisms of androgen-independence and implement life-extending therapies for CRPC.

TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer

PURPOSE Prostate cancer (PCa) becomes resistant to androgen ablation through adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment. Bipolar androgen therapy (BAT), defined as rapid cycling between high and low serum testosterone, disrupts this adaptive regulation in castration-resistant PCa (CRPC). METHODS The TRANSFORMER (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance) study is a randomized study comparing monthly BAT (n = 94) with enzalutamide (n = 101). The primary end point was clinical or radiographic progression-free survival (PFS); crossover was permitted at progression. Secondary end points included overall survival (OS), prostate-specific antigen (PSA) and objective response rates, PFS from randomization through crossover (PFS2), safety, and quality of life (QoL). RESULTS The PFS was 5.7 months for both arms (hazard ratio [HR], 1.14; 95% CI, 0.83 to 1.55; P = .42). For BAT, 50% decline in PSA (PSA50) was 28.2% of patients versus 25.3% for enzalutamide. At crossover, PSA50 response occurred in 77.8% of patients crossing to enzalutamide and 23.4% to BAT. The PSA-PFS for enzalutamide increased from 3.8 months after abiraterone to 10.9 months after BAT. The PFS2 for BAT→enzalutamide was 28.2 versus 19.6 months for enzalutamide→BAT (HR, 0.44; 95% CI, 0.22 to 0.88; P = .02). OS was 32.9 months for BAT versus 29.0 months for enzalutamide (HR, 0.95; 95% CI, 0.66 to 1.39; P = .80). OS was 37.1 months for patients crossing from BAT to enzalutamide versus 30.2 months for the opposite sequence (HR, 0.68; 95% CI, 0.36 to 1.28; P = .225). BAT adverse events were primarily grade 1-2. Patient-reported QoL consistently favored BAT. CONCLUSION This randomized trial establishes meaningful clinical activity and safety of BAT and supports additional study to determine its optimal clinical integration. BAT can sensitize CRPC to subsequent antiandrogen therapy. Further study is required to confirm whether sequential therapy with BAT and enzalutamide can improve survival in men with CRPC.

Outcomes of older men receiving docetaxel for metastatic hormone-sensitive prostate cancer.

82 Background: Most men who die of prostate cancer are older than 70 years, and the impact of therapy in this population is poorly defined. The ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) randomized men of all ages with metastatic hormone-sensitive prostate cancer (mHSPC) to receive androgen deprivation therapy (ADT) with or without docetaxel. Methods: The results of CHAARTED showed an overall survival (OS) benefit for the addition of docetaxel to ADT in men with mHSPC. In a secondary analysis of this trial, we assessed patient characteristics and OS in patients ≥70 years (“older men”) versus <70 years (“younger men”) with Cox proportional hazards models. Additionally, we compared adverse events, therapy completion rate, and subsequent treatment patterns between these two groups using Chi-squared tests. Results: Of the 790 patients enrolled, 177 (22.4%) were ≥70 years. A greater proportion of older men had an impaired performance status (Eastern Cooperative Oncology Group 1-2: 36.7% vs. 28.6%, p=0.038) and prior local therapy (31.7% vs. 25.9%, p<0.001) compared to younger men. Docetaxel + ADT resulted in improved OS in both older and younger men (Hazard Ratio [HR] 0.45, 95%CI: 0.25-0.80 for older men; HR 0.71, 95%CI: 0.53-0.95 for younger men). This treatment benefit was seen for subgroups of older men with high volume disease (HR 0.43, 95%CI 0.23-0.79) and de novo metastatic disease (HR 0.36, 95%CI 0.19-0.69). A similar proportion of older and younger men completed all six cycles of docetaxel (82.6% vs. 87.1%, p=0.28). Rates of grade 3-5 adverse events were similar between older and younger men (36.8% of older men vs. 26.8% of younger men, p=0.69). The rate of any Grade 4-5 adverse events did not differ significantly between older and younger men (14.9% vs. 11.9%, respectively, p=0.46). In the control arm, a smaller proportion of older men received subsequent cancer treatments (34.4% vs. 51.5%, p=0.017) or subsequent docetaxel (25.6% vs. 37.6%, p=0.035) compared to younger men. Conclusions: In summary, older men with mHSPC who were eligible to participate in a clinical trial had similar OS benefit and clinical outcomes compared to younger men when receiving docetaxel chemotherapy + ADT. Oncologists should consider docetaxel chemotherapy as a favorable treatment option for older men with mHSPC who are fit for chemotherapy. Clinical trial information: NCT00309985.

Treating the patient and not just the cancer: therapeutic burden in prostate cancer

Background Prostate cancer (PC) is a leading cause of death in older men. Androgen deprivation therapy (ADT) is considered the standard-of-care for men with locally advanced disease. However, continuous androgen ablation is associated with acute and long-term adverse effects and most patients will eventually develop castration-resistant PC (CRPC). The recent approval of three, second-generation androgen receptor inhibitors (ARIs), apalutamide, enzalutamide, and darolutamide, has transformed the treatment landscape of PC. Treatment with these second-generation ARIs have produced positive trends in metastasis-free survival, progression-free survival, and overall survival. For patients with non-metastatic CRPC, who are mainly asymptomatic from their disease, maintaining quality of life is a major objective when prescribing therapy. Polypharmacy for age-related comorbidities also is common in this population and may increase the potential for drug–drug interactions (DDIs). Method This review summarizes the multiple factors that may contribute to the therapeutic burden of patients with CRPC, including the interplay between age, comorbidities, concomitant medications, the use of ARIs, and financial distress. Conclusions As the treatment landscape in PC continues to rapidly evolve, consideration must be given to the balance between therapeutic benefits and potential treatment-emergent adverse events that may be further complicated by DDIs with concomitant medications. Patient-centered communication is a crucial aspect of alleviating this burden, and healthcare professionals (HCPs) may benefit from training in effective patient communication. HCPs should closely and frequently monitor patient treatment responses, in order to better understand symptom onset and exacerbation. Patients also should be encouraged to participate in exercise programs, and health information and support groups, which may assist them in preventing or mitigating certain determinants of the therapeutic burden associated with PC and its management.

Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer

This chapter summarizes the findings of the landmark Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) trial conducted in men with metastatic, hormone-sensitive prostate cancer comparing docetaxel therapy plus systemic androgen-deprivation therapy to androgen-deprivation therapy alone. It demonstrated improved median overall survival and median time to progression in the chemotherapy arm at the price of some increased severe adverse events.