Rethinking the Prostate Cancer Paradigm in the Urology Community

Raoul S. Concepcion, MD, FACS

As we are all keenly aware, there is not a day that passes when our email inbox doesn’t include news of a genetic discovery that contributes to the ever-expanding body of knowledge in the prostate cancer world. The practicing urologist has to decipher this maelstrom of data, somehow gain a basic understanding of its significance, and determine its clinical utility. Clearly, the world of prostate cancer management has taken on degrees of complexity that none of us ever imagined. We are well past the days of bilateral orchiectomy.

Without question, the urology community is woefully deficient in identifying the patient with advanced prostate cancer who is at risk of developing metastatic disease. Prior to the introduction and commercialization of prostate-specific antigen (PSA) testing, patients with prostate cancer were typically monitored for pain evaluation, serum prostatic acid phosphatase testing, and interval imaging. The advent of PSA testing changed this schema. However, the failure of the urologist, as well as the medical oncologist, to understand the limitations and usefulness of PSA, especially in the setting of the patient on androgen deprivation therapy (ADT), has led to delays in identification of metastases and subsequent institution of superior therapies. There are several examples that highlight this disconnection, which continues to be prevalent.

It has been well documented in a number of trials that among patients who progress beyond ADT to what we now call castration- resistant prostate cancer (CRPC), nearly one-third, many of whom are completely asymptomatic, will actually harbor metastatic disease.¹ The dependence on clinical symptomatology, one of the few determinants of the need for imaging and restaging in the setting of low or slowly accelerating PSA, has been a major challenge for physicians in their clinical practice. As a direct result, many patients are going untreated, despite the plethora of new agents currently available.

Many of us have used first-generation androgen receptor signaling inhibitors/antiandrogens for many years. However, in the setting of metastatic CRPC (mCRPC), these agents as monotherapies have not demonstrated a survival benefit compared with all of the newer therapies approved by the FDA since 2010. Despite this fact, the number of patients who get started on antiandrogens as first-line therapy remains high. Much of this revolves around the misguided notion that drops in PSA, usually very short-lived with these agents in the patient with CRPC, will result in better outcomes. This is far from the truth. Two FDA-approved agents for mCRPC, sipuleucel-T (Provenge) and radium-223 (Xofigo), have significant survival benefit but do not always result in a diminution of PSA.^2,3 Sadly, many providers have refused to utilize these therapies due to this lack of PSA response. Again, there is a refusal to give up previously held beliefs.

Recently, 2 trials have been presented that utilize an intermediate endpoint, metastasis-free survival, to evaluate the efficacy of these newer agents in patients with nonmetastatic CRPC.^4,5 Knowing that PSA was not a good surrogate marker to predict overall survival (OS) in CRPC and that OS has been the gold standard for mCRPC trials, this represents a significant step forward by the FDA in trial design, given the number of potential targeted therapies that are currently being investigated. Hopefully, this breakthrough will allow more oncolytics to enter the market faster as we gain an understanding of resistance mechanisms.

These scenarios highlight the need for clinicians to rethink and challenge their traditional ways of practice and educational needs. In particular, it is imperative that we gain a better understanding of the molecular drivers that result in progression of disease. We will continue to have a cascade of discovery and new information from the many scientists working in this field. To better serve our patients and avoid clinging to tradition, we, as clinical scientists, need to continue to evolve our thinking and approach to patient care.

References

1. Yu EY, Miller K, Nelson J, et al. Detection of previously unidentified metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetastatic, castration resistant prostate cancer. J Urol. 2012;188(1):103-109. doi: 10.1016/j.juro.2012.03.008.
2. Kantoff PW, Higano CS, Shore ND, et al; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411- 422. doi: 10.1056/NEJMoa1001294.
3. Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014;15(7):736-746. doi: 10.1016/S1470-2045(14)70183-4.
4. Hussain M, Fizazi K, Saad F, et al. PROSPER: a phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol. 2018;36(suppl 6S; abstr 3). ascopubs.org/doi/abs/10.1200/JCO.2018.36.6_suppl.3.
5. Smith MR, Saad F, Chowdhury S, Oudard S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418. doi: 10.1056/NEJMoa1715546.