Prostate cancer is the second most common cause of cancer-related death in men. Although the overall survival of patients with metastatic prostate cancer has improved with the addition of second-generation hormone therapy, most men will develop progressive disease, eventually leading to death. Novel therapeutic mechanisms are needed to improve treatments and outcomes in patients with metastatic prostate cancer. Biomarker-driven treatments such as targeted therapies and immuno-oncologic agents are currently under investigation, and may lead to less toxicity and better outcomes for these patients. Here, we review the current use and future direction of these novel therapeutic targets.
Click here to read an expert perspective from Sonia M. Seng, MD.
Prostate cancer is the most common cancer in men in the United States, ranking second to lung cancer among deaths from cancer, with an estimated 29,430 deaths in 2018. The most lethal form of the disease is castration-resistant prostate cancer (CRPC), which occurs with the loss of clinical response to initial androgen deprivation therapy (ADT). The treatment for CRPC has evolved over time, from treatments with a palliative focus to treatments that extend survival. Docetaxel was the first agent found to improve survival in men with CRPC, with a median survival of 19 months.[2,3] There have been five new drugs approved by the US Food and Drug Administration (FDA) for prostate cancer since 2010, which extend survival but are not curative. These new agents include the second-generation hormonal agents abiraterone and enzalutamide, which target the androgen receptor (AR) pathway, as well as non-androgen–targeted therapies, including chemotherapy such as cabazitaxel, DNA-damaging agents such as radium-223, and immunotherapy such as sipuleucel-T. Despite these advances, each class of drugs improves the median survival by only approximately 3 to 4 months, thus stressing the need for novel therapeutic approaches.
Despite the use of ADT in CRPC, cell growth and proliferation continues. The mechanisms that allow cell growth in this clinical state include, but are not limited to, autocrine androgen signaling, AR overexpression, and AR splice variants. Further understanding of these mechanisms has led to the development of the FDA-approved agents (Figure). The aim of this review is to examine the FDA-approved non-androgen–mediatedtherapeutic targets, as well as promising agents in clinical trials for patients with CRPC.
Treatment Options for Metastatic CRPC Patients
The synthetic taxane docetaxel was the first agent found to show a survival benefit in patients with metastatic CRPC, as demonstrated in two phase III trials, the Southwest Oncology Group 99-16 trial and the TAX 327 trial.[2,3] These two studies established the benefit of taxane chemotherapy and set a new standard of care in the treatment of metastatic CRPC. Despite the survival benefit demonstrated with docetaxel, all patients ultimately progress on treatment due to either innate or acquired taxane resistance.
Cabazitaxel was developed due to its low affinity for MDR1 and superior blood-brain barrier penetration compared with paclitaxel and docetaxel.[6,7] Its efficacy was investigated in the second-line setting in the TROPIC trial, which included men with metastatic CRPC who had progressed during or after docetaxel treatment. This phase III study found an increased overall survival of 15.1 months in patients treated with cabazitaxel, compared with 12.7 months in men treated with mitoxantrone. This was the first agent to demonstrate a survival benefit in docetaxel-refractory patients, and this trial led to the FDA approval of cabazitaxel in 2010.
The FIRSTANA trial investigated the use of cabazitaxel vs docetaxel in the first-line setting for metastatic CRPC. Patients were randomized 1:1:1 to cabazitaxel 20 mg/m2 (C20), cabazitaxel 25 mg/m2 (C25), or docetaxel 75 mg/m2 (D75). The median overall survival was 24.5 months with C20, 25.2 months with C25, and 24.3 months with D75. Adverse events ≥ grade 3 occurred in 41.2% of patients treated with C20, 60.1% of those treated with C25, and 46.0% with D75. Febrile neutropenia was most frequently seen in patients who received C25. Overall, this study showed that cabazitaxel is not superior to docetaxel in the first-line treatment of metastatic CRPC. Despite this finding, there are instances when cabazitaxel could be considered instead of docetaxel. Specifically, cabazitaxel was found to have lower rates of grade 3/4 peripheral neuropathy and may be a better option for certain patients.
Advances in cancer immunology have changed the treatment and prognosis for many advanced malignancies. These immunotherapeutic agents include cancer vaccines, immune checkpoint inhibitors, adoptive T-cell therapy, and viral vectors. Sipuleucel-T, an autologous dendritic cell vaccine, was approved by the FDA in 2010 for prostate cancer. After leukapheresis, harvested antigen-presenting cells are exposed to a fusion protein of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (referred to as PA2024) and infused back into the patient. This process is repeated every 2 weeks for 3 cycles. The phase III IMPACT trial randomized men with metastatic CRPC 2:1 to receive sipuleucel-T or placebo and found no significant difference in time to progression, but found an improved median overall survival in the sipuleucel-T group compared with the placebo group (25.8 months vs 21.7 months). Survival appears to be longer in patients with low-volume disease. The exact mechanism by which these patients experienced improvement in overall survival without a difference in time to progression remains unclear. It is possible that the effect that these immune agents provide is delayed beyond initial progression, in comparison with traditional chemotherapy in which a decrease in time to progression is more closely related to overall survival. This study led to the FDA approval of sipuleucel-T for the treatment of asymptomatic or minimally symptomatic patients with nonvisceral metastatic CRPC in 2010.
The use of cancer vaccines, in an effort to stimulate a tumor-directed immune response, is an area of ongoing clinical research and has led to the development of a prostate-specific antigen (PSA)-based vaccine called PSA-TRICOM. This vaccine consists of the vaccinia and fowlpox viral vectors and contains the PSA gene and the costimulatory molecules B7.1, ICAM-1, and LFA-3, referred to as TRICOM. The proposed mechanism of this vaccine is thought to be through the presentation of PSA to immune cells with costimulatory molecules, which enhances a T-cell cytotoxic response. This was first investigated in a phase II trial of men with minimally symptomatic metastatic CRPC randomized 2:1 to PSA-TRICOM and GM-CSF or placebo with an empty vector and GM-CSF. Although this study did not show any difference in progression-free survival, it did show an increase of 25.1 months in median overall survival with PSA-TRICOM compared with 16.6 months with placebo. These findings led to a phase III study; unfortunately, no survival benefit was demonstrated with PSA-TRICOM.[14,15]
Chimeric antigen receptor (CAR) T cells are autologous T cells that are engineered ex vivo to express a recombinant AR. The goal of CAR T-cell therapy is to direct immune activation against the target antigen. CAR T-cell therapy has had recent success in the treatment of hematologic malignancies, with FDA approval for the treatment of refractory diffuse large B-cell lymphoma and refractory B-cell acute lymphoblastic leukemia. Prostate cancer is a viable candidate for CAR T-cell development, since it has specific tumor-associated antigens, including prostate-specific membrane antigen (PSMA) and prostate stem cell antigen (PSCA). A phase I study using PSMA-directed CAR T cells reported that 2 of 5 patients treated obtained a PSA response. A second phase I study using a PSMA-directed CAR T cell is ongoing (ClinicalTrials.gov identifier: NCT01140373). One of the challenges identified in treating metastatic prostate cancer with CAR T-cell therapy is related to the high prevalence of bony disease and the difficulty of recruiting CAR T cells to these lesions, overcoming the immunosuppressive environment.
The success of checkpoint inhibitors that target either cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) or the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis has changed the way we treat many advanced malignancies, and they continue to gain additional indications from the FDA. The potential promise of immunotherapy in the treatment of prostate cancer is based on findings that show a significant T-cell infiltration in prostate tissue. Phase I/II studies of ipilimumab in metastatic CRPC showed efficacy, leading to the phase III CA184-043 trial, which included patients with bony metastases who had progressed on docetaxel therapy. In this study, patients received 8 Gy of radiation to at least one bony site, followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for a maximum of 4 cycles, with the option of maintenance therapy every 3 months in non-progressing patients tolerating treatment. The median overall survival did not meet statistical significance between the ipilimumab and placebo groups (11.2 vs 10.0 months).
However, a subgroup analysis observed an improved overall survival with ipilimumab in patients with more favorable prognostic features, including those without visceral metastasis, those with no increase or a minimal increase in alkaline phosphatase levels, and those without anemia. The phase III CA184-095 trial investigated the safety and efficacy of ipilimumab vs placebo in chemotherapy-naive patients, and found no significant difference in survival between the groups.
PD-1 has been shown to be a target in prostate cancer, since tumor-infiltrating lymphocytes found in prostate cancer have been shown to express PD-1 and PD-L1, albeit at a lower rate than other solid tumors.[23,24] However, in an early study with the anti–PD-1 agent nivolumab, though tumor responses were demonstrated among patients with solid tumors, there were no responses seen in the 17 patients with CRPC. Tumor samples from only two of these patients were tested for PD-L1 expression and were negative. None of these patients received prior treatment with either abiraterone or enzalutamide, which may change the tumor microenvironment. The combination of ipilimumab and nivolumab is currently being investigated in the phase II CheckMate 650 trial (ClinicalTrials.gov identifier: NCT02985957).
Despite this lack of response to immune checkpoint inhibition, Graff et al identified two exceptional responders, raising the hypothesis that AR blockade may enhance response to immunotherapy, perhaps through upregulation of PD-L1.[26,27] A phase II trial evaluated patients who had progressed on enzalutamide; they were given pembrolizumab every 3 weeks for 4 doses in addition to enzalutamide. Three of the first 10 patients enrolled had a remarkable decrease in PSA levels; of the 2 patients with measurable disease, both had a partial response. This unexpected finding may be explained by a study that demonstrated that patients who had progressed on enzalutamide have a significantly increased number of PD-1/2 dendritic cells in their blood compared with treatment-naive patients responding to enzalutamide.. Pembrolizumab may also have activity in prostate cancer patients with microsatellite instability, for which it is FDA approved. It should be noted that only about 2% of CRPC patients are microsatellite instability–high.
Other checkpoint inhibitors are currently being evaluated in CRPC. A phase I study of atezolizumab in patients with metastatic CRPC who had progressed on prior therapy with either enzalutamide and/or sipuleucel-T was recently performed. Of 15 patients, 1 patient had a partial response, 5 patients had stable disease, and 2 experienced a ≥ 50% decrease in PSA and a 12-month overall survival rate of 55.6%. Only 9 of the patients experienced ≤ grade 3 adverse events, and there were no grade 4 or 5 events, demonstrating that atezolizumab was well tolerated and provided long-term disease control in this heavily pretreated population. Currently, a phase III randomized multicenter trial is investigating the combination of atezolizumab with enzalutamide compared with enzalutamide alone in patients who have received prior abiraterone therapy and have either progressed on, are ineligible for, or refused taxane therapy (ClinicalTrials.gov identifier: NCT03016312).
Membrane and Cellular Targets
PSMA is a transmembrane protein that is highly specific for both benign and malignant prostate epithelial cells.[31,32] PSMA is also expressed on vascular endothelium, as well as other epithelial tissues, including salivary glands. PSMA is an ideal therapeutic target, since it is membrane bound, and ligand binding leads to internalization of the molecule. This has led to the development of multiple PSMA-directed therapies, including antibody-drug conjugates. This directed therapy aims to deliver the drug molecules to PSMA expression cells, sparing normal tissues and potential associated side effects. MLN2704 is an antibody-drug conjugate comprised of HuJ591, a humanized anti-PSMA monoclonal antibody, and the microtubule inhibitor DM1. In early-phase studies, a low rate of clinical activity was seen, which was attributed to poor drug delivery secondary to deconjugation of MLN2704. A phase II trial with monomethyl auristatin E, a synthetic antimitotic agent, conjugated with a PSMA monoclonal antibody demonstrated a PSA response > 30% in 30% of patients. Treatment toxicities were common, with 25% of previously taxane-exposed patients developing ≥ grade 3 neutropenia.[35,36]
BIND-014 is a docetaxel-containing PSMA-targeted nanoparticle. These nanoparticles are designed to accumulate in prostate tissue and release docetaxel in a controlled manner.[32,37,38] A phase II study was completed that included 42 docetaxel-naive patients with metastatic CRPC who had previously been treated with abiraterone, enzalutamide, or both. The median radiographic progression–free survival was 7.1 months, with a PSA decline of ≥ 50% seen in 30% of patients. Unfortunately, rates of toxicity were high; the most frequently seen adverse events were fatigue (69%), nausea (55%), and diarrhea (45%), followed by neuropathy, lymphopenia, and anemia. Overall, the toxicity profile and clinical activity of BIND-014 was similar to systemic docetaxel administration, which raised concerns for drug deconjugation and target affinity.[37,38]
Conjugates with radioisotopes allow for targeted delivery of alpha and beta particles to the PSMA-expressing site. Lutetium-177 (177Lu)-PSMA-617 complexes have shown preliminary activity. In retrospective studies, the percentage of patients who experienced a > 50% reduction in PSA levels has been reported to be 30% to 70%. Common side effects included hematologic and salivary gland toxicities. In a phase II trial of 47 heavily pretreated men with metastatic CRPC, patients were given 177Lu conjugated with HuJ591; 36.2% had a > 30% PSA response and a median overall survival of 17.6 months. All patients experienced transient hematologic toxicity, with 46.8% of patients having grade 4 thrombocytopenia. These responses seen in heavily pretreated patients are exciting and have provided the foundation for ongoing prospective clinical trials.
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