expert roundtables

Prostate Cancer: Avoiding Overtreatment and Undertreatment in the Current Era

by Tanya B. Dorff, MD; Robert Dreicer, MD, MS, MACP, FASCO; and Neal D. Shore, MD, FACS

Overview

Our featured experts highlight opportunities to optimize care, focusing on the treatment of metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC).

Q:

What are the concerns in the field right now regarding over- and undertreatment?

Neal D. Shore, MD, FACS

Director, CPI, Carolina Urologic Research Center
Chief Medical Officer, Urology/Surgical Oncology
GenesisCare, US
Myrtle Beach, SC

“There are at least 6 distinct mechanisms of action and many more novel treatments for mCRPC, but data suggest that, on average, patients are availed of relatively few of these treatments before they succumb to mCRPC.”

Neal D. Shore, MD, FACS

When I look at the utilization of combination therapy for our patients with both low- and high-volume mCSPC, I observe underutilization and undertreatment. The CHAARTED trial, as well as multiple arms of the STAMPEDE, ARCHES, ENZAMET, TITAN, and ARASENS trials, have all clearly demonstrated the benefit of combination therapy over androgen deprivation therapy (ADT) monotherapy for patients with mCSPC. All of the contemporary guidelines reflect this standard, yet, in the United States and globally, many urologists and medical oncologists still only seem to be utilizing ADT monotherapy, which is classic undertreatment. This is an issue that must be overcome soon. 

There is evidence for undertreatment in mCRPC as well. There are at least 6 distinct mechanisms of action and many more novel treatments for mCRPC, but data suggest that, on average, patients are availed of relatively few of these treatments before they succumb to mCRPC. If a patient is going to succumb to the disease, does it not seem appropriate that the individual receive as many novel mechanisms of action as possible or enroll in a clinical trial? Further, the sequencing of 1 novel hormonal agent after another is an inefficient strategy. Data from the PROfound, CARD, and PLATO trials, along with the recent VISION trial, suggest that we should be treating patients with therapies that have differing mechanisms of action.

Regarding the overtreatment of prostate cancer, there are several areas to highlight. More patients who have grade groups 1 and 2 localized prostate cancer could probably be undergoing active surveillance. Additionally, we have overutilized testosterone suppression, historically. In biochemical relapse, the decision to initiate testosterone suppression must be weighed very carefully, as there are many trade-offs and side effects associated with testosterone suppression.

Robert Dreicer, MD, MS, MACP, FASCO

Section Head, Medical Oncology
Deputy Director, University of Virginia Comprehensive Cancer Center
Associate Director for Clinical Research
Co-Director, Paul Mellon Urologic Cancer Institute
Professor of Medicine and Urology
University of Virginia School of Medicine
Charlottesville, VA

We are transitioning from a conventional imaging paradigm to a next-generation imaging paradigm. And, with that transition, there is the potential for both under- and overtreatment."

Robert Dreicer, MD, MS, MACP, FASCO

This is a particularly important topic now in the context of prostate-specific membrane antigen positron emission tomography (PSMA PET) imaging. We are transitioning from a conventional imaging paradigm to a next-generation imaging paradigm. And, with that transition, there is the potential for both under- and overtreatment. 

PSMA PET imaging has the potential to provide important clinical information in the setting of prostate-specific antigen (PSA) progression following definitive local therapy. It is also useful in patients with high-risk local disease in the detection of occult metastases. In the mCRPC setting, PSMA PET is performed in consideration of radioligand therapy with lutetium Lu 177 vipivotide tetraxetan. The VISION trial, which led to the recent US Food and Drug Administration approval of lutetium Lu 177 vipivotide tetraxetan, required PSMA-positive disease using Ga PSMA PET/computed tomography.

Despite this important development, we need to remember that when we try to apply findings from newer, more sensitive imaging for patient management decisions, we do so in the setting in which all of our current therapeutics were developed in studies using conventional bone scan and computed tomography imaging, creating the potential risk of both under- and overtreatment. In a patient with biochemical recurrence and some equivocal findings on PSMA PET, not offering curative-intent salvage therapy (eg, prostate bed radiation therapy plus short-term ADT) raises concerns about undertreatment. In contrast, in patients with biochemical failure and no overt metastases on conventional imaging but with equivocal findings on PSMA PET, introducing therapies and toxicities earlier than what we would have done in the past raises concerns about overtreatment. 

Tanya B. Dorff, MD

Associate Professor, Department of Medical Oncology & Therapeutics Research
Section Chief, Genitourinary Disease Program
City of Hope
Duarte, CA

“Regardless of the disease setting that we are aiming to treat, I think that we all consider the patient’s life expectancy, baseline status, and comorbidities as factors that are very relevant to the risk of over- and undertreatment.” 

Tanya B. Dorff, MD

I agree with Dr Dreicer that, largely, PSMA PET imaging could complicate how we categorize patients in earlier disease stages, and that more data are needed in those settings. Additionally, as Dr Shore noted, it seems that the standard of care for treatment intensification in mCSPC has not necessarily translated well into clinical practice, and I do believe that there is considerable undertreatment of both mCSPC and mCRPC.

Regardless of the disease setting that we are aiming to treat, I think that we all consider the patient’s life expectancy, baseline status, and comorbidities as factors that are very relevant to the risk of over- and undertreatment. And there is a need to consider age-associated comorbidities in addition to chronological age to ensure that we do not have an inherent bias that prevents us from applying level-1 evidence to older individuals.

Some clinicians might be hesitant to recommend newer intensification strategies for a patient who is advanced in years. Consider an 80-year-old man with mCSPC. If he is very healthy and has a 10-year life expectancy, he would absolutely benefit from treatment intensification, and it should be offered to him. Conversely, if he has severe comorbidities, treatment intensification might carry a risk of overtreatment, since even the relatively well-tolerated androgen receptor–targeted agents can have negative interactions with certain chronic conditions.

As Dr Dreicer alluded to, there can be uncertainty with nonmetastatic CRPC on conventional imaging in view of equivocal findings using next-generation imaging. PROSPER, SPARTAN, and ARAMIS were large, placebo-controlled, phase 3 trials that showed a significant benefit in metastasis-free survival in men with nonmetastatic CRPC, as determined using conventional imaging, and all 3 trials selected patients based on short PSA doubling time. In this case, I think that the use of PSA doubling time to select patients for therapeutic escalation really highlights the need to incorporate prognostication when we are applying clinical trial data to the patient before us.

References

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Attard G, Borre M, Gurney H, et al; PLATO Collaborators. Abiraterone alone or in combination with enzalutamide in metastatic castration-resistant prostate cancer with rising prostate-specific antigen during enzalutamide treatment. J Clin Oncol. 2018;36(25):2639-2646. doi:10.1200/JCO.2018.77.9827

Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303. doi:10.1200/JCO.20.03488

Davis ID, Martin AJ, Stockler MR, et al; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835

de Wit R, de Bono J, Sternberg CN, et al; CARD Investigators. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206

Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342

George DJ, Sartor O, Miller K, et al. Treatment patterns and outcomes in patients with metastatic castration-resistant prostate cancer in a real-world clinical practice setting in the United States. Clin Genitourin Cancer. 2020;18(4):284-294. doi:10.1016/j.clgc.2019.12.019

Hussain M, Mateo J, Fizazi K, et al; PROfound Trial Investigators. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020;383(24):2345-2357. doi:10.1056/NEJMoa2022485

James ND, de Bono JS, Spears MR, et al; STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377(4):338-351. doi:10.1056/NEJMoa1702900

Kulkarni AA, Rubin N, Tholkes A, et al. Risk for stroke and myocardial infarction with abiraterone versus enzalutamide in metastatic prostate cancer patients. ESMO Open. 2021;6(5):100261. doi:10.1016/j.esmoop.2021.100261

Kyriakopoulos CE, Chen Y-H, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018;36(11):1080-1087. doi:10.1200/JCO.2017.75.3657

Loeb S, Bjurlin MA, Nicholson J, et al. Overdiagnosis and overtreatment of prostate cancer. Eur Urol. 2014;65(6):1046-1055. doi:10.1016/j.eururo.2013.12.062

Marshall CH, Chen Y, Kuo C, et al. Timing of androgen deprivation treatment for men with biochemical recurrent prostate cancer in the context of novel therapies. J Urol. 2021;206(3):623-629. doi:10.1097/JU.0000000000001797

Pisansky TM, Thompson IM, Valicenti RK, D'Amico AV, Selvarajah S. Adjuvant and salvage radiotherapy after prostatectomy: ASTRO/AUA guideline amendment 2018-2019. J Urol. 2019;202(3):533-538. doi:10.1097/JU.0000000000000295

Sartor O, de Bono J, Chi KN, et al; VISION Investigators. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322

Smith MR, Hussain M, Saad F, et al; ARASENS Trial Investigators. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115

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Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382(23):2197-2206. doi:10.1056/NEJMoa2003892

Wang J, Zang J, Wang H, et al. Pretherapeutic 68Ga-PSMA-617 PET may indicate the dosimetry of 177Lu-PSMA-617 and 177Lu-EB-PSMA-617 in main organs and tumor lesions. Clin Nucl Med. 2019;44(6):431-438. doi:10.1097/RLU.0000000000002575

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