Prostate cancer continues to present an enormous unmet burden. In the United States, more than 174,000 new cases will be diagnosed this year.  In addition, almost 10 percent of all male cancer-related deaths will be attributed to prostate cancer¹. Globally, the highest incidence of prostate cancer is observed in the United States, Europe, Australia, Brazil and South Africa. Additionally, in low-income countries, prostate cancer contributes to a major health hazard. Survival rates for prostate cancer in Sub-Saharan Africa are significantly lower than in the United States. For example, the five-year relative survival rate in Uganda is approximately 45 percent as compared to greater than 95 percent in the United States, according to the Surveillance, Epidemiology, and End Results (SEER)². The etiologies for poor prostate cancer survival in Uganda may be from a more aggressive cancer biology, challenges in health care access, limited medications available, or a combination of factors. The challenge of prostate cancer will only continue to increase as Globocan predicts that, by 2040, prostate cancer incidence will increase by over 1 million cases as compared to 2018 levels. 

In 1966, Dr. Charles Huggins won the Nobel Prize in Physiology and Medicine for demonstrating that prostate cancer can be treated with the manipulation of sex hormones. In experiments conducted in the 1940s, which consisted of surgical castration or the addition of female hormones, Dr. Huggins demonstrated that lowering the testosterone levels these could positively impact men affected with prostate cancer. Almost 70 years later, “hormonal manipulation” is the mainstay of any advanced prostate cancer therapy and the foundation of essentially all current treatment strategies. 

In the 1980s, approximately 40 years after Dr. Huggins’ original research, leuprorelin was approved for the treatment of prostate cancer as a gonadotropin-releasing hormone analogue. This “chemical castration” approach was also found to be equivalent in efficacy and safety to surgical castration. There are currently numerous luteinizing hormone-release hormones (LHRH) medications that lower testosterone including goserelin, triptorelin, histrelin, among others.  

The “first-generation” antiandrogen medications were also developed in the 1980s. These agents, including bicalutamide and nilutamide, were generally given in addition to LHRH therapies for men with advanced prostate cancer. Although generally safe, the first-generation antiandrogen agents had a relatively small clinical impact. Although there was continued interest in developing novel antiandrogen strategies, it was another 25 years before the second-generation antiandrogens were FDA-approved.

In the 1990s and 2000s, there was significant clinical development for solid tumors, especially lung and breast cancer. There was, however, less interest in prostate cancer clinical development. This changed dramatically after Dr. Ian Tannock’s publication in 2004 in the New England Journal of Medicine. Dr. Tannock’s article demonstrated a survival advantage for docetaxel plus prednisone over mitoxantrone plus prednisone in men with castrate-resistant prostate cancer. This landmark study energized pharmaceutical companies, government agencies, investigators and patients to invest enormous resources for prostate cancer. Over the last 15 years, the results of these efforts have produced dramatic therapeutic advances utilizing a variety of approaches at a breakneck speed.  

As the treatment landscape for prostate cancer changes, the nomenclature describing these patients continues to evolve. Sub-categories have been created for prostate cancer to describe the patient’s disease status based on location of spread, disease phenotype, castrate-resistant status, tumor pathology, genetic variation, and other variables. To organize these disease features for clinical research, entities such as the Prostate Cancer Working Group 3 (PCWG3) have established guidelines for drug development³. This standardization of clinical features helps in the development and execution of clinical trials comparing similar patient populations.  

Advanced prostate cancer treatments 

Once the patient has demonstrated that his cancer has spread outside of the prostate, systemic treatment options are considered. For non-metastatic, castrate-sensitive disease patients, options include observation or luteinizing hormone-releasing hormone (LHRH) therapy. For subjects who have no metastases seen on an imaging scan yet develop a rising prostate-specific antigen (PSA) on LHRH and are considered castrate-resistant, treatment options include the addition of second-generation antiandrogens (apalutamide, darolutamide or enzalutadmide).  

A significant number of all prostate cancer patients ultimately develop metastatic disease. Therapeutic options for patients with metastatic disease who are still responsive to castrate treatment include LHRH with or without second generation antiandrogens (apalutamide, darolutamide or enzalutadmide) or the addition of docetaxel chemotherapy. The majority of treatment options are currently reserved for patients with castrate-resistant metastatic prostate cancer (mCRPC). These include second generation antiandrogens (abiraterone acetate, enzalutamide), chemotherapy (cabazitaxel, docetaxel) immunotherapy (sipuleucel-T), and radioisotopes (radium-223). Patients with specific genetic alterations, such as BRCA1/2 or PALB2 may benefit from PARP inhibitors (olaparib). Additionally, supportive agents to minimize bone loss such as denosumab or zoledronic acid are used. 

Over the last 15 years, the addition of these novel therapies for prostate cancer have made a significant positive impact for patients. Essentially all the agents detailed have demonstrated an improvement in overall survival, progression free survival, or both. An example includes the greater than 1-year overall survival improvement in castrate-sensitive metastatic prostate cancer patients when they receive docetaxel chemotherapy⁴. In a similar patient population, abiraterone acetate has also demonstrated an increase in overall survival compared to placebo^5.  

Multiple trials have shown benefit for patients with mCRPC. One such example is enzalutamide, given to men with mCRPC prior to chemotherapy, which demonstrated a significant progression-free survival as compared to placebo⁶. In men with prior docetaxel chemotherapy, cabazitaxel was superior to mitoxantrone for mCRPC patients⁷.   

The exact sequencing of prostate cancer therapies is not completely defined. For example, one question that is asked in metastatic castrate-sensitive prostate cancer is whether patients should receive docetaxel, a second-generation antiandrogen, or both? Additional questions include: Which second-generation antiandrogen should a patient receive first in mCRPC? Should radium-223 be given before or after chemotherapy? In general, patients are given individualized care based on their disease characteristics, response to therapy, performance status, among other factors.  

Emerging areas

Even with multiple agents now approved for the systemic treatment of prostate cancer, much work remains. Focuses of clinical development include overcoming resistance to antiandrogen agents, improved vaccine therapies, development of more effective radioisotopes, and less toxic chemotherapy agents. Promising areas for novel therapeutics include immunotherapy agents as well as targeting the prostate-specific membrane antigen.

Although a variety of immunotherapy agents, including those that target programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), are approved for a variety of solid tumors, none are yet approved by regulatory agencies for the treatment of prostate cancer. Multiple agents are currently in clinical development in prostate cancer including pembrolizumab, nivolumab, and ipilimumab, among others. Although initial studies have failed to demonstrate meaningful activity with single agent PD-L1, current trials are demonstrating promise with combination strategies. These ongoing trials include immunotherapy agents partnered with antiandrogens, PARP inhibitors, and chemotherapy, as well as combing both PD-L1 and CTLA-4 agents. 

The prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed on nearly all prostatic tissue including carcinoma. Initial clinical use for PSMA testing includes helping diagnose prostate cancer from benign tissue using histopathological stains. The current focus for PSMA research programs includes targeted radioisotopes for PET imaging for diagnostic purposes and targeting PSMA as a therapeutic strategy. As of August 2019, Clinicaltrials.gov lists over 200 clinical trials targeting PSMA. 

There are multiple isotopes in development that target PSMA using PET/CT imaging for the diagnosis of localized and/or metastatic prostate cancer. These include 68Ga-PSMA, [18F]PSMA, rhPSMA, as well as other agents. Although many of these agents may eventually replace standard nucleotide and CT scans for the imaging of prostate cancer patients, no PSMA agent has regulatory approval yet. However, this may change in the future based on ongoing PSMA PET/CT clinical trials. 

PSMA presents an ideal targeted therapy for prostate cancer. Although a PSMA-directed approach is quite promising, there is extensive competition in this space. Multiple approaches are currently ongoing including antibodies directed at PSMA, radioisotopes that have a therapeutic ligand, and CAR-T cell. In addition, trials are examining PSMA directed agents in combination with immunotherapy (pembrolizumab), antiandrogens (enzalutamide) as well as other targeted therapies 

Future challenges

We have recently seen an extraordinary number of developments for prostate cancer treatments which creates challenges for novel drug development. There are multiple factors to consider for both biotechnology and pharmaceutical companies developing agents in this space. One area to consider is which patient disease state to pursue. Currently, there are over one hundred clinical trials in mCRPC and significantly less addressing earlier stage disease such as non-metastatic castrate-resistant patients. Although there are significantly different regulatory requirements for approval for these varying stages, pursuing earlier stage patients will offer a much less crowded clinical development strategy. 

The development of a multi-disciplinary team is essential for successful prostate cancer drug development. Partnering with experts in regulatory affairs, logistics, market access, and medical expertise is mandatory. Although the space is crowded, there is still plenty of room for drugs to treat prostate cancer if they are developed with a smart and holistic clinical development strategy.

Matthew Cooney is the Senior Medical Director and Oncology Lead, Global Medical Services, Parexel.

References

1. Siegel RL, Miller KD, Jemal A.  Cancer statistics, 2019. CA Cancer J Clin. 2019 Jan;69(1):7-34.  doi: 10.3322/caac.21551. Epub 2019 Jan 8.  
2. Gondos A, Brenner H, Wabinga H, Parkin DM. Cancer survival in Kampala, Uganda. Br J Cancer.  2005 May 9;92(9):1808-12.  
3. Sher, et al. J Clin Oncol 34, no. 12 (April 20, 2016) 1402-1418. DOI: 10.1200/JCO.2015.64.2072.  
4. Sweeney, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med 2015; 373:737-746. DOI: 10.1056/NEJMoa1503747. 
5. Fizazi, et al. Abiraterone plus prednisone in metastatic, castrate-sensitive prostate cancer. N Engl J Med 2017; 377:352-360. DOI: 10.1056NEJMoa1704174. 
6. Beer, et al. Ezalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371:424-433. DOI: 10.1056/NEJMoa1405095.  
7. de Bono, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; Vol 376, Issue 9747, P1147-1154.