Charles G. Drake, MD, PhD

Susan Halabi, PhD

ALTHOUGH THE National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) strongly influence the management of advanced prostate cancer, they do not always reflect actual clinical practice. It turns out that in the real world, there are multiple areas of disagreement and/or divergent interpretations of existing data among experts regarding the optimal management of patients with metastatic/recurrent prostate cancer. 

An international panel of 60 experts explored 10 critical aspects of management and attempted to reach a consensus that could be clinically useful for decision-making.¹ Their findings (published in European Urology) reflect real-world practice and reveal areas of strong/reasonable agreement as well as areas that are unsettled, suggesting that the day-to-day management of prostate cancer often depends on the clinician’s preferences/beliefs/biases, even in areas where there is level 1 evidence to support a specific intervention. 

“There are several areas where data are still emerging or are not definitive. This consensus statement presents a global picture of how surgeons, radiation and medical oncologists, and pathologists in the United States and Europe are currently taking care of men with advanced prostate cancer,” stated Charles G. Drake, MD, PhD, one of the panelists, and Director of Genitourinary Oncology at NewYork-Presbyterian/ Columbia University Medical Center, New York. 

The topics covered include high-risk localized and locally advanced prostate cancer, the role of imaging, bone-targeted therapy, molecular characterization of blood and tissue, genetic counseling/ testing, side effects of systemic treatment(s), and global access to prostate cancer drugs. This article focuses on some of the high points regarding areas of disagreement and agreement, as well as topics for which there is no high-level evidence to guide practice. 

Striking Observations 

“WHEN I LEFT the conference, I was struck by several things. One was the difference between Europe and the United States in the use of positron-emission tomography [PET] prostate-specific membrane antigen imaging, which is a next-generation imaging modality. Imaging will need to evolve in the United States. Additionally, I was also surprised that level 1 evidence from clinical trials was being interpreted differently around the world, particularly regarding the use of chemohormonal therapy in men with low-volume metastatic disease,” Dr. Drake commented. 

“I was surprised level 1 evidence from clinical trials was being interpreted differently around the world, particularly regarding the use of chemohormonal therapy in men with low-volume metastatic disease.”

— Charles G. Drake, MD, PhD

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“The discussion on the use of imaging in men treated with surgery or radiation who have a rising prostate-specific antigen [PSA] level was enlightening,” Dr. Drake continued. In the United States, a bone scan and a computed tomography (CT) scan are recommended to document and/or quantify metastatic disease, but these modalities have several limitations in detecting metastases as well as in monitoring treatment response. In Europe, next-generation imaging using PET with a prostate-specific membrane antigen tracer has gained significant traction, although clinical trials have not yet shown the impact of this modality on clinical outcomes. 

“It was surprising to me that there was fairly strong agreement that PET prostate-specific membrane antigen should be considerered as an advanced modality,” he noted. 

For locally advanced prostate cancer, there was a lack of consensus regarding the best imaging modality to use: 41% of panelists voted for standard imaging with a combination of CT and bone scintigraphy, whereas 47% voted for next-generation imaging methods (37% for PET with prostate-specific membrane antigen or other tracers). 

In the setting of recurrent oligometastatic disease following local treatment of prostate cancer with curative intent, 78% agreed that next-generation imaging should be used. For de novo oligometastatic disease, 72% voted for next-generation imaging. 

Regarding the recommended tracer in the case of PET/CT scan in men with apparent oligometastatic castration-naive disease, 76% voted for prostate-specific membrane antigen as a tracer, 10% voted for fluciclovine as a tracer, 6% voted for choline, and 4% voted for any of the three tracers. 

In the United States, PET prostate-specific membrane antigen is considered investigational and is not widely available, he noted. He is hopeful this will change. 

Chemohormonal Therapy 

“THE DISCUSSION about chemohormonal therapy in men with metastatic prostate cancer was fascinating,” Dr. Drake said. There was general agreement that men with de novo high-volume metastatic disease should receive chemotherapy plus androgen-deprivation therapy. However, based on the subgroup analyses of the CHAARTED² and GETUG³ trials, only 30% of participants agreed that chemotherapy should be added to androgen-deprivation therapy for most men with low-volume disease, 65% voted to use it in select patients, and 9% voted not to use it. 

At the meeting, Susan Halabi, PhD, of Duke Cancer Institute, Durham, North Carolina, made the point that the data regarding low-volume disease were based on subgroup and retrospective analyses, which are generally underpowered in terms of statistical significance. 

There was disagreement on how to manage the hormone-naive patient following surgery or radiation as primary treatment who relapses with bulky high-volume metastatic disease: Should these men receive chemotherapy, as suggested by results of the CHAARTED trial? Only 74% of the panelists said yes, which was not considered consensus. “I would have expected more than 90% to agree, based on level 1 evidence,” Dr. Drake admitted. 

There was also disagreement on how to manage a patient treated with primary surgery but who several years later develops low-volume disease (ie, oligometastasis—up to four metastatic lesions). “Only 19% of panelists said they would give chemohormonal therapy, yet CHAARTED suggests chemohormonal therapy prolongs survival,” revealed Dr. Drake. 

Another area of disagreement was in the primary management of oligometastatic disease. Should these patients receive local treatment with stereotactic radiotherapy? “There is really no level 1 evidence to support definitive treatment of local recurrent lesions,” Dr. Drake said. “Logically, treatment makes sense, but many clinicians said they would not treat without level 1 evidence, whereas many experienced oncologists do treat. There is lots of room for discussion here, as well as for definitive clinical trials.” 

Areas of Agreement 

AGREEMENT WAS strong regarding what should be included in the pathology report. Also, there was reasonable agreement on which nodes to remove surgically during a radical prostatectomy. 

Another area of consensus was related to patients who present with metastatic disease upfront who should not receive docetaxel. In general, panelists agreed docetaxel should not be used in patients with significant liver dysfunction, neuropathy, or very low platelet counts. 

“This consensus took place before the presentation of two phase III studies at the 2017 ASCO Annual Meeting, which showed that patients with upfront metastatic disease had improved survival when treated with abiraterone acetate (Zytiga) plus androgen-deprivation therapy vs androgen-deprivation therapy alone,” he noted. These trials were STAMPEDE and LATITUDE.^4,5 

There was also good agreement on the first-line treatment of asymptomatic castration-resistant prostate cancer. Of the panelists, 86% said these patients should receive abiraterone or enzalutamide (Xtandi) before using chemotherapy. Only 8% said that sipuleucel-T (Provenge) was a good option. “This was surprising to me. Sipuleucel-T is approved by the U.S. Food and Drug Administration (FDA) for the treatment of asymptomatic metastatic castration-resistant prostate cancer, based on randomized controlled trials showing a survival advantage,” Dr. Drake commented. 

Anti–PD-1 Treatment 

PEMBROLIZUMAB (KEYTRUDA), an anti–programmed cell death protein 1 (anti–PD-1) checkpoint inhibitor, was not included in the discussion, because at the time the panel met, it was not considered an option. However, in June of this year, the FDA approved pembrolizumab for the treatment of any tumor type with microsatellite instability (MSI)—including metastatic prostate cancer. “These tumors have a high mutational load, likely providing multiple targets for immune recognition,” Dr. Drake commented. 

Dr. Drake was excited about this new treatment option. “This only pertains to 3% to 5% of all prostate cancer patients, but MSI tumors are aggressive, from what we know so far, they are likely to respond to anti–PD-1 therapy,” he said. More studies of pembrolizumab will be forthcoming, including evidence on the best way to test tumor tissue for MSI. ■

DISCLOSURE: Dr. Drake has been a paid consultant for Astellas, AstraZeneca, Compugen Inc, Dendreon Inc, Roche/Genentech, Harpoon, Janssen, Merck, Potenza, and Tizona. Through sponsored research agreements managed by Johns Hopkins Univeristy, Dr. Drake’s lab has received funding from Aduro Biotech, Bristol-Myers Squibb’s IIoN Network, and Janssen. Dr. Halabi reported no conflicts of interest. 

REFERENCES 

1. Gillessen S, Attard G, Beer TM, et al: Management of patients with advanced prostate cancer: The report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2017. Eur Urol (in press). Available at http://www.europeanurology.com/article/S0302-2838(17)30497-9/fulltext. Accessed August 1, 2017. 

2. Sweeney CJ, Chen YH, Carducci M, et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 373:737-746, 2015. 

3. Gravis G, Boher JM, Joly F, et al: Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: Impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial. Eur Urol 70:256-262, 2016. 

4. James ND, De Bono JS, Spears MR, et al: Adding abiraterone for men with high-risk prostate cancer starting long-term androgen deprivation therapy: Survival results from STAMPEDE. 2017 ASCO Annual Meeting. Abstract LBA5003. Presented June 3, 2017. 

5. Fizazi K, Tran N, Fein LE, et al: LATITUDE: A phase III, double-blind, randomized trial of androgen deprivation therapy (ADT) with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naive prostate cancer patients. 2017 ASCO Annual Meeting. Abstract LBA3. Presented June 4, 2017.