Prostate cancer is the second most common cancer in men.It is a cancer that occurs in the prostate — a small walnut-shaped gland in men that produces the seminal fluid that nourishes and transports sperm. While some types of prostate cancer grow slowly and may need minimal or even no treatment, others are aggressive and can spread quickly. Prostate cancer that’s detected early, when it’s still confined to the prostate gland, has a better chance of successful treatment. But malignant growths can be a threat to life as they can spread to nearby organs and tissues, such as the bladder or rectum, and can also metastasize to other parts of the body like lymph nodes or bone. Although it can be removed, sometimes it grows back. Treatment side effects can lead to incontinence, erectile dysfunction, depression, fatigue, and infertility.

WuXi AppTec Communications has been highlighting companies conducting novel research into different diseases, but another key to finding treatments for unmet medical needs are active disease research organizations and patient advocacy groups, which help provide financial support for research, provide useful patient information on how to get help, and represent the patients in an advocacy role.

To coincide with a new WuXi AppTec series about prostate research, we spoke with Jonathan W. Simons, MD, President and CEO of the Prostate Cancer Foundation (PCF), for an overview about the current state of prostate research and the pathways to future treatments and cures.

Dr. Simons is an internationally recognized physician-scientist, oncologist and acclaimed investigator in translational prostate cancer research. Prior to joining the PCF in 2007, he was Distinguished Service Professor of Hematology and Oncology at the Emory University School of Medicine and Professor of Biomedical Engineering and Materials Sciences at the Georgia Institute of Technology. Dr. Simons is the Founding Director of the Winship Cancer Institute at Emory University in Atlanta and Co-Director of the National Cancer Institute Center for Cancer Nanotechnology Excellence at Emory and Georgia Tech.

WuXi AppTec: What progress has been made in diagnosing and treating prostate cancer since the founding of the Prostate Cancer Foundation (PCF) 25 years ago?

Dr. Simons: The PCF has supported the research leading to every major practice-changing advance against prostate cancer since its founding in 1993. This includes early research and development for nearly every life-extending drug approved by the U.S. Food and Drug Administration (FDA) for prostate cancer since 2004.

Without a doubt, the prognosis for men diagnosed with prostate cancer at any stage has never been more encouraging. Recent advances enable men with prostate cancer to live longer, more productive lives – and when detected early through routine physical exams and minimally invasive blood tests, prostate cancer is nearly 100 percent treatable. Nearly 100 percent of men diagnosed with prostate cancer in the local or regional stages will be disease free after five years.

Equally important is the fact that discoveries in prostate cancer now extend to saving lives in more than 18 other forms of cancer, including breast, myeloma, colon, lung, ovarian, melanoma, pediatric neuroblastoma, bladder, and thyroid cancers. Because the PCF is focused on precision medicine, we are funding research that targets cancers based on their genomic alterations and not the organs from which they came, and therapies that help men with metastatic prostate cancer have been shown to be effective in more than 73 other forms of human cancer. Over the last two decades, the PCF has worked tirelessly and effectively to promote public awareness about the disease to the reduction in the U.S. death rate from prostate cancer by more than 50 percent.

WuXi AppTec: And as a follow up, there seems to be a lot of confusing advice coming from the community about what type of prostate testing is most effective. Can you comment? 

Dr. Simons: The PCF has always stressed that the question of screening is a personal and complex one, and we believe in strategic and personalized screening. The decision to undergo routine prostate specific antigen (PSA)-based screening in men with a normal risk aged 55 to 69 should be an individual one that includes a discussion about the potential benefits and harms of screening.

The PCF believes that every man should be able to talk with his doctor about whether prostate cancer screening is right for him. Additionally, it is the PCF’s position that for men with a family history of lethal breast cancer, ovarian cancer, or pancreatic prostate cancer in a first-degree relative, 40 is the age at which a conversation with a health provider to discuss the potential benefits and harms of prostate cancer screening should begin. In the African-American community, we encourage men at 45 to pay attention to their prostate health and prostate cancer risk and take the opportunity to talk with their doctors about the pros and cons of prostate cancer screening.

Above all, the PCF believes there is no ‘one-size-fits-all’ approach to screening. We generally support the recommendation made by the United States Preventive Services Task Force against prostate cancer screening in men over the age of 70, although we acknowledge that this age-based recommendation may not be appropriate for all men over the age of 70 and advocate for a personalized approach that takes into account health, values, and preferences.

WuXi AppTec: What are the hot targets today in the field of drug development for prostate cancer?

Dr. Simons: Poly-ADP ribose polymerase (PARP) and prostate-specific membrane antigen (PSMA) are two of the “hottest targets” in the field of drug development for prostate cancer today.

A study presented recently at the 2019 European Society for Medical Oncology (ESMO) Congress reported positive results from a Phase 3 clinical trial testing the PARP inhibitor olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) who have alterations in certain DNA damage repair (DDR) genes, a result which will likely lead to a new FDA approval. Roughly 20 to 30 percent of mCRPC patients harbor these DDR gene mutations in their tumors and thus may benefit from PARP-inhibition. This trial of olaparib is the first positive Phase 3 “precision medicine” clinical trial testing a targeted therapy in men with advanced prostate cancer with defined mutations.

PARP inhibitors were first approved by the FDA as treatments for BRCA1/2-deficient breast and ovarian cancer in 2014. However, PCF-funded studies demonstrated that BRCA1/2 and PARP are also important in prostate cancer.

Prostate-specific membrane antigen is a protein on the surface of prostate cancer cells, and is a compelling cell surface drug target. The PCF is supporting research into many new treatments for prostate cancer that target PSMA, including radionuclide therapy, a treatment that brings radiation directly to tumors, and chimeric androgen receptor (CAR) T cells, a form of personalized immunotherapy. Prostate-specific membrane antigen is also a very good target for PET imaging tracers, and PSMA-PET imaging has been demonstrated to be significantly more sensitive than current imaging methods for detecting sites of prostate cancer throughout the body. The PCF anticipates that PSMA-PET imaging will likely be FDA approved by 2020.

WuXi AppTec: What are the prospects for treating the disease in its early stages? Will drugs ever be a substitute for surgery and radiation?

Dr. Simons: Early potentially lethal prostate cancer if untreated can be cured by not one but two different modalities: radiation therapy or surgery.

Eventually, the PCF believes most advanced prostate cancer can be intercepted when it is micro-metastatic and the total burden of cancer in a patient’s body is at its lowest number. If caught early, prostate cancer is 100 percent treatable. Early, strategic detection is thus so important. Early prostate cancer can be treated by not one but two modalities: radiation and surgery. Surgery and radiation therapy remain the standard treatment for localized prostate cancer. But other experimental treatment options have recently become available. As time goes on and the benefits of these treatment options are better understood, it’s possible that they may be reasonable alternatives for certain patients.

For now, none of these are seen as standard treatment for localized prostate cancer because they lack support from large randomized clinical investigations in comparison with successful radiation or surgery.

WuXi AppTec:  What are the regulatory challenges in evaluating early stage prostate cancer treatments?

Dr. Simons: The process of discovering, developing, and delivering new therapies has myriad challenges. In order for the FDA to approve a new therapy, an improvement in length or quality of life due to the therapy must first be demonstrated in clinical trials. The “overall survival” (OS) endpoint, which measures the length of time from randomization to death from any cause, is the gold standard for measuring the impact of a treatment on length of life and the goal line for calling a new treatment curative. However, in localized prostate cancer, reaching an OS endpoint can require 10 to 15 years – a prohibitive timeframe for pharmaceutical companies. This fact has translated into only limited improvements being made in the treatment of early, aggressive prostate cancer in the last decade.

For patients urgently awaiting treatments and cures, addressing these regulatory challenges is vital. For this reason, the PCF identified this issue as a critical unmet need, and in 2012, supported the establishment of a working group called ICECaP (Intermediate Clinical Endpoints of Cancer of the Prostate). Led by Dr. Christopher Sweeney of the Dana-Farber Cancer Institute, this is an international collaborative initiative to undertake the arduous task of identifying an intermediate clinical trial endpoint that can accurately predict OS but can be obtained much earlier in the course of the disease.

WuXi AppTec: Is clinical trial participation by patients a challenge? If so, how does the PCF encourage participation?

Dr. Simons: The first 1,000 men cured of incurable advanced prostate cancer will be in a clinical trial. The road to cures runs through clinical trials.

The PCF is the go-to source for information about the latest investigational clinical trials driven by PCF-funded science. In addition to publishing the Prostate Cancer Patient Guide, a comprehensive health guide for prostate cancer patients compiled with the contributions of top-tier doctors and researchers in prostate cancer, PCF.org is the center for must-have resources for prostate cancer patients. It focuses all of the information available about contemporary prostate cancer research, treatment, lifestyle factors, and precision clinical trials.

To further improve access to information that can improve outcomes by getting patients on “the right track” as soon as possible, the PCF has also launched a prostate cancer clinical trial finder in collaboration with Smart Patients. Because finding a trial can be confusing for patients, the PCF has custom-curated trials that may be specifically relevant to men with prostate cancer. The tool allows men to search based on their disease state, stage, and their geographical location.

WuXi AppTec: What are researchers learning about the causes of prostate cancer? How is it different from other cancers?

Dr. Simons: Over the past 25 years, more than 50 hereditary DNA mutations (genetic mutations that run in families) have been discovered that may increase the risk of developing certain cancers. The most famous that you may have heard of are the BRCA1 and BRCA2 mutations that increase risk for breast and ovarian cancer.

Prostate cancer has long been recognized to have a familial component. In fact, of all human cancers, prostate cancer is the most common running by hereditary 57 percent among family members, with 40 percent of prostate cancer attributable to genes that run in families. If you have received a prostate cancer diagnosis, it’s important to speak with your family about risk, prevention, and screening. Having a father or brother with prostate cancer increases a man’s risk of developing prostate cancer. The genes that cause this risk have been extensively studied and are complex and need more research.

WuXi AppTec: How does the PCF support research and drug development?

Dr. Simons: The PCF is unique in its innovative approach to medical research funding. The PCF identifies the most promising “first-in-field” early research ideas and attracts brilliant individuals and teams of scientists early in their careers to the PCF’s Global Research Enterprise. By channeling resources directly to the world’s top scientific minds, the PCF is able to cut through red tape, speed scientific breakthroughs, and deliver new treatments to patients. The PCF funds a variety of different kinds of projects that vary in focus, scope, and duration: PCF Challenge Awards fund teams of scientists working on critical unmet needs for advanced prostate cancer; PCF Young Investigator Awards jumpstart research programs for early-career scientists and researchers; and, PCF researchers connect globally to exchange information and share scientific data in real time.

Since its inception the PCF has been a pioneer in new drug development, providing key funding for FDA-approved treatments that improve survivorship. Having recruited more than 5,000 of the best physician-scientists in more than 21 countries, many of the most important discoveries in the fight against prostate cancer since 1993 have resulted from PCF funding or coordination. Thanks in large part to the work of PCF-funded researchers, the number of drugs approved to treat prostate cancer doubled – from just six drugs approved in nearly 30 years to another nine drugs approved in just nine years. Of those nine medicines, eight were FDA-approved because they actually prolong patients’ lives, rather than simply ease their symptoms. As of early 2019, there are now a total of 21 drugs approved by the FDA for treatment of prostate cancer, with even more in the pipeline.

WuXi AppTec:  What are some of your most recent research funding efforts?

Dr. Simons: Prostate cancer is the most frequently diagnosed cancer among veterans. In 2016, the PCF committed $50 million over five years to create Veterans Affairs (VA) Centers of Excellence that deliver innovative, best-in-class prostate cancer care to veterans. More than half of the PCF’s Precision Oncology funds have already been used to stand up ten Centers of Excellence and fund the research of numerous VA physician-scientists. The platform created by the PCF will be used to build Centers of Excellence for other cancers as well.

WuXi AppTec: What is the best strategy for developing new prostate cancer drugs?

Dr. Simons: Collaborative teams comprised of young scientists is the fastest route for research and development to end death and suffering from a disease. The contribution, or loss, of even the single greatest researcher, isn’t likely to make or break the attainment of a cancer cure. That achievement will come from the global community of a great team of researchers. These repositories of accumulated intellectual, physical, and financial resources represent the “social capital” of medical progress. The PCF has laid the cornerstone for at least four major social capital initiatives involving this community.

The PCF has changed how research is funded to harness the power of teams. Our research awards are designed to attack major problems in prostate cancer biology and treatment by creating synergistic teams of individuals with diverse intellectual capabilities who otherwise might simply conduct isolated research in their own silos they require constant unpublished data sharing. The PCF began seeding this field with individual research awards in 1993. As traditional funding sources have picked up these programs, we’ve adopted a strategy of directing current and future PCF funding to more effective team science. This strategy has resulted in the formation of collaborative teams who are able to take research from bench to bedside rapidly.   

WuXi AppTec: What are the top three impediments to delivery of better medicines, faster and cheaper to patients?

Dr. Simons: Our greatest challenge of all of the many challenges is less than five percent of men with advanced prostate cancer participate in clinical trials. Our second challenge for advanced disease is that we still need to better understand how to stop prostate cancer cells from evolving in real time to become resistant to our new promising therapies. Cancer cell “evolutionary” resistance is the killing mechanism of fatal cancers.

WuXi AppTec: What are your thoughts relating to focal therapy and prostate cancer?

Dr. Simons: “Focal” therapies are treatments that target just a region of the prostate thought to have the tumor, instead of treating the entire prostate gland. None of these therapies have yet been proven in large randomized clinical trials to have the same long-term success as surgery or radiation therapy in clinical trials. Claims about them must be viewed with caution. They are still considered experimental treatments. The likelihood of recurrence is high with focal therapy due to the fact that in more than 60 percent of cases prostate cancer is actually “multi-focal,” meaning even if the biopsy and/or MRI showed the cancer to be in only one area, there is likely tumor in many areas of the prostate.

WuXi Apptec: What would be the one thing that has the most potential to lead a paradigm shift from treatment to cure in prostate cancer drug development?

Dr. Simons: One of the most promising areas that has the potential to lead a paradigm shift from treatment to cure is the field of immunotherapy. Historically, the problem with curing cancer has been the uncanny ability of cancer cells to reprogram themselves after treatment and hide from the immune system. The promise behind immunotherapy is that when properly activated, the immune system has the potential to evolve as quickly as the tumor and seek out and kill tumor cells anywhere they are hiding in the body. In many types of cancer, immunotherapy has resulted in long-term remissions and even cures in patients with advanced metastatic disease who would otherwise have died from their disease. Numerous ongoing research studies and clinical trials are being conducted around the world trying to discover newer immune cell activations and optimize immunotherapy to treat the many forms of advanced prostate cancer.