Challenges Persist in Deploying ADT in Prostate Cancer

Ashley E. Ross, MD, PhD

In 1941, Charles Brenton Huggins, MD, observed that prostate cancer could be controlled by hormone-directed treatments, a discovery for which he was awarded half the Nobel Prize in Physiology or Medicine in 1966.¹ Since then, hormone therapy focused on androgen deprivation, and referred to as androgen deprivation therapy (ADT) or androgen suppression therapy, has become a key prostate cancer treatment, particularly in the setting of advancing prostate cancer.

ADT can include surgical castration (ie, orchiectomy) or medical/chemical castration using luteinizing hormone-releasing hormone (LHRH) agonists, LHRH antagonists, and/or CYP17 inhibitors. In the United States, medical/chemical castration is often preferred for cosmetic reasons and because its effects are reversible; however, these treatments can have a significant impact on quality of life (QOL). Ensuring patients reap the greatest benefits from these treatments with the least risk of adverse effects and negative impact on QOL, clinicians need to make careful decisions about when to initiate these treatments and how best to administer them.

Optimal Timing of ADT Initiation

During a recent OncLive Peer Exchange^®, a group of prostate cancer experts discussed several controversies and challenges surrounding the use of ADT in patients with hormone-sensitive prostate cancer. Key areas of discussion focused on optimal timing for initiating ADT; the need for better identification of patients requiring earlier ADT retreatment and a recently approved imaging agent that has the potential to serve this purpose; goal testosterone levels, which have been aggressively lowered in Europe; use of intermittent versus continuous ADT; and triggers for restarting ADT.Based on current data, several panelists felt it is best to delay initiation of ADT following biochemical recurrence. “Traditionally, at our institution, we would wait until metastatic progression in most cases—watch the PSAs rise and do routine imaging, sometimes yearly and other times once we got to a certain rise threshold,” said Ashley E. Ross, MD, PhD.

“But if the PSA doubling time is <6 months, I’m very worried that they’re having pending progression and will also start therapy,” he said, citing an important paper by Freedland and colleagues that found a PSA doubling time to be a significant risk factor for time to prostate-specific mortality.²

“In a setting where we don’t have clinical trials, we do try to delay initiation as long as possible,” concurred Alicia K. Morgans, MD, MPH. “And certainly, we consider patient preferences and anxieties in all of that, too,” she said.

The panelists acknowledged that there are significant challenges with discussing delaying treatments with patients, who are often anxious about following a watch-and-wait approach. “Telling a patient ‘your disease is growing, we haven’t seen it yet, but don’t worry, let it grow bigger and then we’ll treat when you have developed metastasis’ is a very foreign concept—one that for the last 5 to 10 years we’ve been trying to educate patients on,” said Jorge A. Garcia, MD.

Better Identification of High-Risk Patients and Recurrence

He suggested there is likely to be a benefit to initiating treatment earlier, rather than delaying until metastasis is detectable on conventional imaging, but that ADT-related toxicities generally prohibit this approach. He also suggested that once technologies are available that would more objectively identify the metastasis, it would likely be better to intervene earlier rather than delaying treatment until disease becomes more advanced.“We need to identify patients who will have the most aggressive disease because just having small-volume micrometastatic disease doesn’t necessarily mean this will be an aggressive disease,” said Morgans. “My hope is that imaging and other technologies to identify those patients with aggressive disease will be here shortly and we’ll be able to integrate those technologies into care.”

The panelists briefly discussed imaging modalities and agents under investigation or recently approved that are showing promise in revolutionizing the ability to detect prostate cancer recurrence. Once such compound, Blue Earth Diagnostics’ fluciclovine F 18 injection, was approved by the FDA on May 31, 2016.³ The agent, which is used with positron emission tomography, detects the upregulation of amino acid transport that occurs in prostate cancer.

In the studies that led to fluciclovine F 18’s approval, independent readers unaware of patients’ prostate cancer details correctly identified recurrence in 77% of cases, and when cancer occurred outside of the prostate, it was correctly identified in 90% of cases.³

Testosterone-Lowering Goals

Because such new imaging techniques are more sensitive and specific than conventional agents, they are likely to “create a lot of questions” on how to treat patients, said moderator Raoul S. Concepcion, MD, who anticipates these agents will help further move clinicians toward the therapeutic management of oligometastatic disease. However, because these agents are still in their infancy, it is unclear how they will impact patient care and outcomes.A serum testosterone <50 ng/dL has been considered the desired castrate level, and these levels are still supported by the most recent NCCN Prostate Cancer Guidelines.⁴ However, European guidelines have lowered recommendations to <20 ng/dL following data indicating improved outcomes in these patients.⁵

The historic castrate level of <50 ng/dL was determined more than 40 years ago.⁵ “[At the time] we didn’t have sensitive enough assays to test testosterone...and all of our clinical trials at this current time are based on this testosterone level,” said Daniel R. Saltzstein, MD. “Retrospective and prospective trials show there is a delay in development of castration-resistant prostate cancer, an improvement in survival, and a decreased risk of death when you can suppress testosterone to <20 ng/dL.

Intermittent Versus Continuous ADT

“Now that we know in an orchiectomized male that the normal testosterone level is about 15 ng/dL, I think, even in the United States, we will strive to achieve a much lower level of testosterone in the future,” he added.The panelists largely agreed on the use of intermittent versus continuous ADT. In general, they use intermittent ADT for patients with biochemical recurrence (ie, no evidence of metastatic disease on conventional imaging) and continuous ADT for patients with detectable metastatic disease, taking costs, side effects/toxicity, and patient preferences into consideration.

“In the biochemical recurrent state, I use intermittent ADT...in the metastatic space, based on the Hussain data from SWOG,⁶ I use continuous ADT unless the patient is experiencing profound side effects,” said Morgans.

In the landmark SWOG study, a 10% increase in the relative risk of death was observed with intermittent ADT versus continuous ADT in men with metastatic hormone-sensitive prostate cancer.⁶ Despite such findings, Morgans said she would not rule out intermittent therapy for these patients. “These patients are living with this disease for years, and it’s my responsibility to not only keep them alive, but to make sure they experience that in the best way possible,” she explained.

“When you think about rising PSA syndrome, one of the biggest challenges that I think we face is that the data we have for ADT in the biochemical recurrence space is all over the map,” acknowledged Garcia. “In my opinion, the best data that we have [to support intermittent ADT], and perhaps the data that I follow the most, is Crook and colleagues’ data from Vancouver.”⁷

Crook and colleagues’ study found intermittent ADT to be noninferior to continuous therapy in patients with a PSA level >3 ng/mL >1 year after primary or salvage radiotherapy for localized prostate cancer, with an overall survival of 8.8 years versus 9.1 years, respectively; patients with evidence of distant metastasis were excluded from the study.⁷ Additionally, several QOL factors improved with intermittent therapy, including better scores for hot flashes, desire for sexual activity, urinary symptoms, and fatigue.

Garcia noted the rationale for using intermittent therapy is to maximize QOL, which hinges on patients recovering their testosterone levels. Subsequently, he recommends clinicians monitor testosterone in addition to PSA levels in these patients to ensure they are truly benefitting from this approach.

Triggers for Restarting ADT in Biochemical Recurrence

“Once I know testosterone has recovered, then I know how long it’s going to take for the patient to recover their QOL, and that is the period that I think patients value the most,” he said, noting that it can take some patients many months to years to recover their testosterone levels following cessation of ADT. “If I must shut down testosterone again within 3 months, the patient really is not benefitting from intermittent therapy, but if it takes me 1 or 2 years to restart ADT, then the patient is benefitting from that approach.”Despite most panelists agreeing on when to use intermittent versus continuous ADT, the experts differed on which triggers they use to potentially restart ADT in their patients with biochemical recurrence.

“I’ve tended to use a testosterone rising to >50 ng/dL, which is now unfortunate, to determine when to potentially restart an individual on hormone therapy,” said Saltzstein. He indicated this might not be an ideal trigger, likely due to the newer data showing testosterone levels <20 ng/dL being better castrate targets.

Take-Home Message

In contrast, Morgans said she uses a variety of PSA-related triggers at her center, depending on the circumstance. “Sometimes I use doubling time, sometimes I use PSA back to the level at which we started therapy, and sometimes I have an absolute threshold—I don’t want to go >20 ng/mL—so it really depends on the patient’s situation, and if it’s that variable even within my own practice, I’m sure that it’s even more variable at various institutions,” she said.ADT has been a cornerstone of prostate cancer treatment and will continue to have a prominent role in treating hormone-sensitive prostate cancer for the foreseeable future, even as therapeutic options continue to expand. Timing of ADT, triggers for restarting ADT, and use of continuous versus intermittent ADT are key factors that can affect patient outcomes and warrant careful consideration. Until more definitive data and better technologies are available to guide ADT decision making, treatment should be individualized based on cost, side effect profile/toxicities, and patient factors, including preferences.

References

1. Charles Brenton Huggins, MD, Nobel laureate in urology, 1901—1997. William P. Didusch Center for Urologic History website. http://urologichistory.museum/content/collections/uropeople/huggins/p1.cfm. Accessed December 13, 2016.
2. Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA. 2005;294(4):433-439. doi: 10.1001/jama.294.4.433.
3. U.S. FDA approves Blue Earth Diagnostics’ Axumin^TM (Fluciclovine F 18) injection after priority review for PET imaging of recurrent prostate cancer [news release]. Oxford, England, and Burlington, MA: Blue Earth Diagnostics Ltd; May 31, 2016. http://www.businesswire.com/news/home/20160531005713/en/U.S.-FDA-Approves-Blue-Earth-Diagnostics%E2%80%99-Axumin%E2%84%A2. Accessed December 13, 2016.
4. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer. NCCN Evidence Blocks^TM. Version 3.2016. https://www.nccn.org/professionals/physician_gls/pdf/prostate_blocks.pdf. Updated May 26, 2016. Accessed December 14, 2016.
5. European Association of Urology. Guidelines on Prostate Cancer. https://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf. Updated March 2015. Accessed December 14, 2016.
6. Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013;368(14):1314-1325. doi:10.1056/NEJMoa1212299.
7. Crook JM, O’Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med. 2012;367(10):895-903. doi:10.1056/NEJMoa1201546.