Konrad H. Stopsack, MD, MPH
Philip Kantoff, MD
A MAN in his early 70s sits in our office. His general health is good, and he is feeling well. Yet he is deeply worried. Four years ago, when his prostate-specific antigen (PSA) level rapidly increased after radical prostatectomy and subsequent radiation therapy, he was started on androgen-deprivation therapy. However, over the past year, despite a castrate level of testosterone, his PSA level has increased from undetectable to 5.6 ng/mL. Fortunately, no metastases were visible on today’s bone scan and computed tomography.
Can we alleviate this patient’s fears that his next scans will show metastases? Can we prevent or delay the onset of symptoms of metastatic cancer? And can we help him live longer?
With the results of the PROSPER trial—which were reviewed in the August 10, 2018, issue of The ASCO Post—we now have a second U.S. Food and Drug Administration (FDA)-approved treatment option for this patient.1 PROSPER investigators specifically enrolled patients like ours. All 1,401 patients had castration-resistant prostate cancer without detectable metastases on standard imaging but very short PSA doubling times. Enzalutamide (Xtandi), compared with placebo, reduced the rate of metastasis development by an impressive 71%.
So, the answer to the first question is a resounding Yes—enzalutamide is an effective drug that prolonged the time to radiographic disease progression by a median of almost 2 years.
How enzalutamide will affect quality of life and clinical symptoms for men with nonmetastatic castration-resistant prostate cancer is not known yet. There was no suggestion at the time of publication that enzalutamide treatment would improve quality of life or slow or delay its decline.
Patients’ Concerns: Rising PSA Levels and Treatment Side Effects
THIS MAY not be a surprise since the only cancer-associated symptom of nonmetastatic castration-resistant disease is potentially the anxiety associated with a rising PSA level. Yet we have some reason to believe that enzalutamide may be beneficial with respect to cancer-related symptom endpoints. The SPARTAN trial, which tested a similar nonsteroidal antiandrogen, apalutamide (Erleada), in a similar patient population, did show a lower rate of symptomatic disease progression compared with placebo. Data on symptomatic disease progression have not been reported from PROSPER but are eagerly awaited.
Our patient is clearly interested in acting on his rising PSA level and in reducing the risk that his next scans show metastases. Yet he does also worry about enzalutamide’s side effects. His friend, who has already been receiving enzalutamide for metastatic castration-resistant prostate cancer, has some increased fatigue and is finding it more challenging to perform his activities of daily living. PROSPER confirms the well-known side effects of the newer antiandrogen therapies to be real and common. A total of 1 in 11 men suffered a fall or fracture due to enzalutamide, and enzalutamide caused fatigue in about one-fifth of men.
Does Prolonged Time to Metastasis Equal Longer Survival?
WILL ENZALUTAMIDE help our patient live longer in this context (than if it is used when metastases are radiographically evident)? We do not know yet whether prolonged time to metastasis will translate into longer overall survival. In localized prostate cancer, metastasis-free survival is a strong surrogate endpoint for overall survival, as shown by the ICECaP Working Group. In metastatic castration-resistant prostate cancer, as shown in the COU-302 and PREVAIL trials, the time to radiographic disease progression correlated well with overall survival.
Whether this holds true in nonmetastatic castration-resistant prostate cancer remains to be seen. In the first report from PROSPER, only 12% of patients had died. The estimate of enzalutamide’s effect on overall survival was a hazard ratio of 0.80, but there is at present substantial uncertainty that this will hold up (95% confidence interval, 0.58–1.09).
“Thoughtful clinical judgment and an informed patient will be needed to decide between the different treatment options for advanced prostate cancer.”— Konrad H. Stopsack, MD, MPH, and Philip Kantoff, MD
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Balancing Potential Benefits and Risks
REGARDLESS OF what effect enzalutamide has on overall survival in the PROSPER trial population, its use and the data’s generalizability to clinical practice will depend on patient and tumor characteristics. For our patient who has a rapidly rising PSA level, anxiety about his PSA level, and no comorbidity that would predispose him to adverse events from enzalutamide, our choice may be easier. For another man with a slowly rising PSA level or significant comorbidity, the risks of longer and more profound androgen deprivation may outweigh the benefits of postponing radiographic disease progression.
Thus, the clinical context will mandate earlier intervention or not. Moreover, the proper sequencing and combinations of therapies still remain unclear in advanced prostate cancer. Absent head-to-head trials between different therapies and their combinations, results from the international IRONMAN registry of men with advanced prostate cancer will hopefully shed some light on what sequences and combinations of therapies are best for whom. In the meantime, thoughtful clinical judgment and an informed patient will be needed to decide between the different treatment options for advanced prostate cancer. PROSPER has added a valuable option to our toolbox. ■
Dr. Stopsack is Research Associate, The Philip Kantoff Lab, Memorial Sloan Kettering Cancer Center, and Dr. Kantoff is Chair, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York.
DISCLOSURE: Dr. Stopsack reported no conflicts of interest. Dr. Kantoff has served as a consult or advisory to Seer, Bavarian Nordic, Genentech/Roche, Thermo Fisher Scientific, Sanofi, OncoCellMDX, Context Therapeutics, Progenity, Druggablity Technologies, Tarveda Therapeutics, New England Research Institutes, GE Healthcare, Merck, Metamark Genetics, BIND Biosciences, and Janssen; he has patents, royalties and other intellectual property with Composition and Methods for Screening and Diagnosis of Prostate Cancer, Methods for Predicting Likelihood of Responding to Treatment Composition and Methods for Screening and Diagnosis of Prostate Cancer, Wolters Kluwer, Royalties, Up-to-Date Royalties, Methods and Kits for Determining Sensitivity to Cancer Treatment, Predicting and Treating Prostate Cancer, Method for Predicting the Risk of Prostate Cancer Morbidity and Mortality, Somatic ERCC2 Mutations Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma (Patent), Drug Combinations to Treat Cancer, Chromosome Copy Number Gain as a Biomarker of Urothelial Carcinoma Lethality; expert testimony for Janssen; stock and other ownership interests with Seer, Context Therapeutics, Tarveda Therapeutics, Druggablity Technologies, Placon, and Bellicum Pharmaceuticals; and travel, accommodations, and/or expenses from Sanofi.
1. Hussain M, Fizazi K, Saad F, et al: Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med 378:2465-2474, 2018.