Highly effective tools, such as immunotherapeutic agents, have emerged for the treatment of patients with a wide range of malignancies. However, they have demonstrated relatively limited benefit in the treatment of patients with prostate cancer. Intensive research is under way to identify what factors limit the efficacy of immune-based therapies in prostate cancer and to determine how to more effectively leverage immunotherapy to treat men with this disease.

As positive data continue to accumulate, it is becoming clear that there may indeed be a future where immunotherapeutics play a vital role in prostate cancer treatment. However, this will depend on the ability to identify patient-specific factors that can predict response to immune-based therapies, determine the optimal disease setting to use them, and establish which treatments to combine for maximum therapeutic effect.

For many cancers, genomic alterations within tumor cells result in the production of novel proteins known as neoantigens, which can be recognized by the immune system and produce powerful tumor-directed immune responses.

 Unfortunately, in prostate cancer, tumor mutational burden characteristically is low. The resulting effect is that there is frequently lack of antigens on prostate cancer cells capable of eliciting an effective immune response.

 In order to overcome this, investigators have developed an array of vaccine strategies designed to promote an immune attack against the normal antigens expressed on prostate cells. This approach has arguably been the most effective immunotherapeutic strategy in prostate cancer to date and led to the FDA-approved treatment sipuleucel-T (Provenge), which is still in use.

Sipuleucel-T is an autologous dendritic-cell vaccine designed to stimulate a T-lymphocyte response against cells expressing prostatic acid phosphatase, a prostate-specific protein expressed on the majority of prostate adenocarcinomas. It was approved for use in patients with metastatic castrate-resistant prostate cancer (mCRPC) in 2010 based on the results of the phase 3 IMPACT trial (NCT00065442), which demonstrated a 4-month improvement in overall survival (OS) with sipuleucel-T treatment compared with placebo (25.8 vs 21.7 months, respectively).

 Unfortunately, despite this approval and OS benefit, widespread use of sipuleucel-T has been hindered by limitations in patient eligibility (they must have asymptomatic or minimally symptomatic disease), lack of a pharmacodynamic biomarkers (no effect on prostate-specific antigen [PSA] levels), high cost (nearly $100,000 for entire treatment course), and treatment inconvenience (requires leukapheresis followed by reinfusion with each cycle). As a result, the effect of sipuleucel-T on patient care has ultimately been modest, at best, and there continues to be room to improve on this treatment approach.

Two other notable vaccines that have been developed for the treatment of patients with prostate cancer are rilimogene galvacirepvec (PSA-TRICOM; PROSTVAC-VF) and GVAX. Unlike sipuleucel-T, which uses dendritic cells as a vector for the vaccine, PSA-TRICOM and GVAX use allogeneic vectors to stimulate immune destruction of prostate cells. Specifically, PSA-TRICOM uses viral vectors (vaccinia and fowlpox) in a prime-boost strategy, whereas GVAX is composed of 2 irradiated allogeneic prostate cancer cell lines (LNCaP and PC-3), which constitutively express granulocyte-macrophage colony- stimulating factor.

Early phase trials of PSA-TRICOM were highly encouraging, with a phase 2 trial (NCT00078585) demonstrating an improvement in median overall survival of 25.1 months among patients who received PSA-TRICOM compared with 16.1 months among those in the placebo arm.

 The subsequent phase 3 PROSPECT trial (NCT01322490), however, failed to confirm a survival benefit for PSA-TRICOM treatment. As a result, this therapy was ultimately not approved for patient use.

Similar to PSA-TRICOM, the GVAX vaccine also had promising results in early phase trials, which were ultimately followed by 2 disappointing phase 3 trials—VITAL-1 (NCT00089856) and VITAL-2 (NCT00133224).

 As a result, GVAX does not have an approved indication.

Although phase 3 trial outcomes for PSA-TRICOM and GVAX along with the practical challenges of sipuleucel-T may have tempered some of the enthusiasm for vaccine therapy, there also has been evidence that some patients with prostate cancer can derive tremendous benefit from this treatment strategy. In the case of sipuleucel-T, there have been reports of patients who have experienced dramatic and durable responses to treatment, suggesting that there may be patient-specific factors that are relevant to the vaccine response.

 It is not clear which specific factors are relevant and future research may help to guide the targeting of these therapies to those patients who are most likely to respond. 

Additionally, although the above-mentioned trials focused on patients in the castrate-resistant setting, there are data suggesting that vaccines may be more effective in the early stages of prostate cancer when disease burden is low and tumors are less aggressive.

 Vaccines may need to be combined with other therapies, such as immune-directed or standard-of-care treatments, to overcome the immunosuppressive environment within prostate tumors.

 Investigators continue to explore these approaches, as well as other novel vaccine concepts, at the preclinical and clinical stages and have already demonstrated intriguing results. Additional time will be required to see which, if any, of these approaches will prove to be effective in late phase trials.

Because of the immense success of immune checkpoint inhibitors (ICI) in solid and hematologic malignancies, these therapies have been extensively evaluated in prostate cancer as well. At present, pembrolizumab (Keytruda), which received tumor agnostic approval in 2017 for microsatellite instability–high/mismatch repair–deficient (dMMR) tumors, is the only ICI with FDA approval for prostate cancer.

 Subsequent studies have supported the use of pembrolizumab in this patient population; however trials evaluating pembrolizumab in unselected patients with prostate cancer have yet to demonstrate a clear role for this agent.

 The largest of these studies is KEYNOTE-199 (NCT02787005), a phase 2 study that evaluated pembrolizumab treatment in multiple cohorts of patients with metastatic castration-resistant prostate cancer (mCRPC). The first 3 of these cohorts evaluated pembrolizumab monotherapy in patients who had been treated with docetaxel chemotherapy and 1 or more targeted endocrine therapies. The next 2 cohorts evaluated the combination of pembrolizumab plus enzalutamide (Xtandi) in patients with mCRPC who had progressed on enzalutamide therapy.

Data from this study have not been overwhelmingly positive thus far; however, there have been some suggestion of antitumor activity for pembrolizumab. For instance, although the objective (≤ 6%) and PSA (≤ 8%) response rates to pembrolizumab monotherapy were low in the first 3 cohorts, there did appear to be some evidence that in those who did have a response, the responses were durable.

 In the enzalutamide plus pembrolizumab cohorts, the objective response rate was better (12%), signifying possible synergy with the combination approach. The disease control rate (51%), 12-month PFS rate (17%-23%), and time to next anticancer therapy (> 9 months) also suggested possible benefit with the combination.

Data evaluating ICIs with other therapies come from another multicohort study, KEYNOTE-365 (NCT02861573), which combined pembrolizumab with olaparib (Lynparza), docetaxel, and enzalutamide in men with mCRPC in a phase 1b/2 approach. The most updated PSA and objective response rates for pembrolizumab in this study were 9% and 8%, 28% and 18%, and 22% and 12% in combination with olaparib, docetaxel, and enzalutamide, respectively.

Data from other ICIs, including ipilimumab (Yervoy) and nivolumab (Opdivo), also have suggested that a combination therapy approach may be needed in order for ICIs to be successful in prostate cancer. These agents have had minimal success in trials as monotherapies but have demonstrated promise in combination with each other as well as with other therapies in prostate cancer. For example, CheckMate 650 (NCT02985957) is currently evaluating the combination of ipilimumab and nivolumab in men with mCRPC who have progressed after at least 1 second-generation hormone therapy. Interim results presented at the 2019 American Society for Clinical Oncology Genitourinary Cancers Symposium demonstrated overall and PSA response rates of 26% and 18%, respectively, in men who were docetaxel naïve, and 10% and 10%, respectively, for men post docetaxel. In patients with a PD-L1 expression level of at least 1%, the overall response rate increased to 50% and 25% for men who were pre- and post docetaxel, respectively.

Unfortunately, these exciting results were somewhat marred by the high rates of adverse events (AEs), which included rates of grade 3/4 events that exceeded 50%. To address these toxicities, dose and schedule modifications have been implemented in patients still receiving treatment in this ongoing trial.

Patients with strong immunogenic signatures also have provided support for the use of ipilimumab and nivolumab, specifically in data from the phase 2 NEPTUNES trial (NCT03061539). NEPTUNES evaluated the ICI combination in men with mCRPC who had at least 1 of the following: dMMR, DNA damage repair deficiency, or a high level (> 20%) of tumor-infiltrating lymphocytes. In the results presented at American Association for Cancer Research 2021 Annual Meeting, 28.6% of participants had a radiologic response, a PSA response of at least 50%, conversion of circulating tumor cells at 9 weeks, or combination of any of the 3.

Further data for ICIs in prostate cancer come from trials investigating the use of atezolizumab (Tecentriq). The phase 3 IMbassador250 trial (NCT03016312 ) compared enzalutamide plus atezolizumab with enzalutamide alone in patients with mCRPC who had progressed on abiraterone and docetaxel or were not candidates for chemotherapy. At the interim analysis, no difference was noted between the 2 groups in terms of overall survival, which was the study’s primary end point.

 These findings, in addition to the higher rates of AEs in the combination arm (77.8% vs 51.1%), ultimately led to early termination of trial. Fortunately, more promising outcomes were reported in the basket phase 1b COSMIC-021 trial (NCT03170960), which evaluated cabozantinib (Cabometyx) in combination with atezolizumab. In the 44 eligible patients with mCRPC, the objective response rate was 32%, 2 patients experienced a complete response, and the overall disease control rate was 80%.

Taken as a whole, data from these trials and others suggest that, as with vaccines, the future role of ICIs in prostate cancer will likely depend on identifying the right timing, patient population, and therapeutic combination. A wide array of approaches and combinations are under investigation and data from many of these trials are anticipated over the next few years. This information will almost assuredly have a major effect on the types of roles and subsequent studies for ICIs in the coming years.

A wide array of additional immunotherapeutic strategies also are under investigation. However, data from these approaches are much less robust. Two of the more intriguing strategies are chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engagers (BiTEs). Both of these strategies work by directing engaging T cells with tumor cells. In CAR-T cell approaches, this is accomplished by engineering an individual’s T cells to express a receptor for a tumor antigen. BiTEs, on the other hand, are bispecific monoclonal antibodies, which bind to both T cells and tumor cells and bring them into direct contact.

Although each of these approaches has been successful in hematologic malignancies, the challenge of overcoming an immunosuppressive tumor microenvironment have limited their efficacy in solid tumors.

 Strategies to overcome these barriers are under investigation in a range of solid tumors, including in prostate cancer. Although the role of immunotherapeutics in prostate cancer treatment is currently quite limited, studies have demonstrated that administering immunotherapies in the right context can result in a substantial treatment effect. Ongoing studies will hopefully help to clarify which immune-based therapies have a role in prostate cancer treatment and how best to utilize them for maximum patient benefit. The results of these studies over the next few years are eagerly anticipated.

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Articles

Highly effective tools, such as immunotherapeutic agents, have emerged for the treatment of patients with a wide range of malignancies.

David Kosoff, MD

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Immunotherapeutics Aim for Larger Role in Prostate Cancer