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ASCO issues recommendations on second-line hormonal therapy for castration-resistant prostate cancer

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April 25, 2017

A castrate state should be maintained indefinitely in men who develop castration-resistant prostate cancer despite castrate levels of testosterone, according to a provisional clinical opinion issued by ASCO.

The provisional clinical opinion focuses on the use of second-line hormonal therapy for chemotherapy-naive men who have castration-resistant prostate cancer, including those who are asymptomatic with only biochemical evidence of disease to those who have document metastases but minimal symptoms.

“We hope that this [provisional clinical opinion] will offer clinicians and patients timely direction to help inform treatment planning and shared decision-making,” Eric A. Singer, MD, MA, FACS, urologic oncologist at Rutgers Cancer Institute of New Jersey and co-chair of the ASCO expert panel that developed the recommendations, said in a press release.

The goal for the treatment of castration-resistant prostate cancer — or hormone-sensitive prostate cancer that recurs or progresses despite first-line androgen deprivation therapy — is palliation and avoidance of chemotherapy. Results from clinical trials have shown various second-line treatments — including abiraterone acetate (Zytiga, Janssen Oncology) and enzalutamide (Xtandi; Astellas, Medivation), both which are FDA approved for pre-and postdocetaxel treatment in patients with castration-resistant prostate cancer — slow cancer growth and lead to a better quality of life.

In addition, sipuleucel-T (Provenge, Dendreon), a nonhormonal agent, has also been approved in the prechemotherapy setting.

Despite the changing landscape of therapy, data are still limited and challenges remain for clinicians on how to manage and treat patients.

“In the last few years we have seen an unprecedented number of new systemic therapies showing improvements in survival and quality of life for men with castration-resistant prostate cancer,” Katherine S. Virgo, PhD, adjunct professor in the School of Public Health at Emory University and co-chair of the ASCO expert panel, said in the release. “However, due to a lack of guidelines on second-line hormonal therapy for chemotherapy-naive patients, there has been uncertainly regarding the optimal treatment among clinicians.”

Therefore, Singer, Virgo and colleagues conducted a systematic review of six randomized controlled clinical trials conducted between 2000 and 2014 to update ASCO guidelines.

Based on their analysis, the expert panel recommends:

  • A castrate state be maintained “indefinitely” for men who develop castration-resistant prostate cancer regardless of castrate levels of testosterone;
  • Second-line therapies be offered to chemotherapy-naive men with M0 castration-resistant prostate cancer at high risk for the development of metastases;
  • Second-line treatment not be given to chemotherapy-naive men with M0 castration-resistant prostate cancer at low risk for the development of metastases;
  • Second-line hormonal treatment — abiraterone acetate plus prednisone, or enzalutamide — should be offered, along with palliative care, to chemotherapy-naive men with castration-resistant prostate cancer and evidence of metastases;
  • Men with M0 castration-resistant prostate cancer and low risk for the development of metastases should undergo PSA evaluation every 4 to 6 months, whereas men with M0 castration-resistant prostate cancer at high risk or with radiographic evidence of metastases should undergo evaluation every 3 months;
  • A bone scan with CT or MRI of the abdomen and pelvis should be offered if a patient undergoes imaging. The frequency of imaging should be determined by patient symptoms;
  • Radiographic imaging should not be offered to men with castration-resistant prostate cancer and a rising PSA unless radiographic findings could change treatment selection or if symptoms develop; and
  • Routine surveillance radiographic restaging only be used in patients for whom PSA is not a reliable marker of the disease.

The panel noted that the primary limitation was the lack of data from the phase 3 randomized controlled trials. Because the guideline focused on second-line hormonal therapy for chemotherapy-naive patients with M0 and M1 castration-resistant prostate cancer, the panel wrote that updates are anticipated as recommendations are put into practice.

“Further studies of cost and quality-of-life implications of second-line, third-line and so forth hormonal therapies are needed to aid oncologists in discussing treatment options with patients,” the panel wrote. – by Melinda Stevens

Disclosures: Singer and Virgo report no relevant financial disclosures. Please see the full guideline for a list of all other authors’ relevant financial disclosures.

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Min Yuen Teo, MD
Perspective

Howard I. Scher, MD
Perspective

In its provisional clinical opinion on second-line hormonal therapy in men with chemotherapy-naive castration-resistant prostate cancer, the panel provided an overview of the therapeutic landscape in this space over the last decade. The convened experts performed a comprehensive evaluation of the literature with established consensus-reaching methodology, and provided thoughtful interpretation of the results relative to the questions raised. Notable is the relatively small number of trials that met the standards for inclusion, and how few of the early trials provided results that affected practice. This likely is a reflection of the difficulty developing drugs in this space given the long survival times relative to postchemotherapy-treated cohorts, and the lack of intermediate endpoints short of survival that could lead to regulatory approval.

In the past decade — in large part through an understanding of the mechanisms of resistance and a commitment of the prostate cancer research community, including industry, academia, government, regulatory bodies, foundations, philanthropy, patients and their advocates — there have been completed and appropriately powered phase 3 trials with data on which to base treatment recommendations and therapeutic decisions. The result is that both abiraterone acetate in trial AA-302, and enzalutamide in PREVAIL — agents that target two oncogenic drivers of tumor growth, the upregulated androgen-biosynthetic machinery that increases intratumoral androgen levels, and overexpressed androgen receptor — are approved standards of care in the prechemotherapy setting. Both were shown to be effective and approved first in the postchemotherapy setting based on a survival endpoint, and in the prechemotherapy setting using a coprimary endpoint of radiographic PFS and OS. Trials designed to compare combinations of these two classes of drug relative to monotherapy (abiraterone acetate plus enzalutamide vs. enzalutamide alone, or abiraterone acetate plus apalutamide [Janssen] vs. abiraterone acetate alone) are fully accrued, and the results eagerly awaited.

It is important to note that the second-line patient population we are seeing now is changing. Antiandrogen withdrawal is rarely an issue as long-term first-generation antiandrogen use has been replaced with abiraterone or enzalutamide. Since the reporting of PREVAIL and AA-302 trials, many men in the second-line metastatic castration-resistant prostate cancer setting may have already received docetaxel in the noncastrate setting based on the CHAARTED and STAMPEDE trial results, and abiraterone based on the LATITUDE and STAMPEDE results. It is uncertain whether the response to further hormonal manipulation in castration-resistant prostate cancer will be the same following prior use of these agents.

An additional factor that likely will lead to even earlier use of these agents is the increasing availability of functional PET imaging agents such as 11C-choline, 18F-fluciclovine and 18F or 68Ga prostate-specific membrane antigen, leading to upstaging of patients previously considered to have biochemical (PSA) recurrence.

Both of these factors may limit the generalizability of the abiraterone and enzalutamide registration trial results, highlighting the need to continue to support and enroll patients on trials specifically designed for these more contemporary cohorts defined as noted in the Prostate Cancer Working Group 3 recommendations, on the basis of the prior systemic therapies they have received, and for early definitive readouts of efficacy to accelerate regulatory approvals and inform how best to utilize them in practice.

References:

Gillessen S, et al. Eur Urol. 2017;doi:10.1016/j.eururo.2017.06.002.

Scher HI, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2015.64.2702.

Min Yuen Teo, MD

Memorial Sloan Kettering Cancer Center

Howard I. Scher, MD

Memorial Sloan Kettering Cancer Center
Weill Cornell Medicine

Disclosure:Teo reports no relevant financial disclosures. Scher reports nonfinancial support from Janssen and Medivation, personal fees from Astellas and Sanofi, and research funding from Janssen Diagnostics, Janssen Pharmaceuticals and Medivation.