A panel of experts during an OncLive PeerExchange® provided practical definitions for biochemical recurrent hormone-naïve nonmetastatic, metastatic hormone-naïve advancing, nonmetastatic castration-resistant, and metastatic castration-resistant prostate cancer.
Raoul S. Concepcion, MD, FACS
Changes in prostate cancer(PC) screening protocols have led to an evolution in the type of disease that physicians are encountering when patients first enter the clinic, a panel of experts said during a recent OncLive Peer Exchange®. “We are seeing, especially in the urology office, patients coming in not having been PSA [prostate specific antigen] screened, higher Gleason patterns, and metastatic disease. And, obviously, they’ve not been hormonally treated up until this point,” Raoul S. Concepcion, MD, said. This has led to a more aggressive treatment stance that includes early combination hormonal therapy and chemotherapy, he said.
PC remains the most commonly diagnosed malignancy in US men.1 In 2015, there were an estimated 3,120,176 US men living with PC, and 164,690 new cases are anticipated in 2018.1 Although PC incidence and mortality rates have steadily decreased since the early 1990s, the reported incidence of metastatic disease has increased.2 One study reported a 72% increase in metastatic disease paired with a 37% decrease in low-risk PC from 2004 to 2013 among a sample of >700,000 men with a PC diagnosis.3 This trend has largely been attributed to changes in US screening protocols.4,5
In 2008, the US Preventive Services Task Force (USPSTF) recommended against routine PSA screenings for men aged ≥70 years and in 2012 recommended against routine PSA-based screenings for men of all ages.4 The USPSTF has since softened its stance, currently recommending against routine PSA-based screenings in men aged ≥70 years but for screening men aged 55 to 69 years if they express a preference for screening after being counseled about its potential harms, such as the risks of false-positives and the potential for overtreatment (Table).6 With fewer PC cases being diagnosed at low-risk stages, healthcare providers have been tasked with treating more advanced PC cases.
As a result, advanced PC is being redefined, the panel said during the OncLive Peer Exchange®. “We’ve traditionally thought of PC as a single continuum and it’s not,” Daniel J. George, MD, said. The panel provided practical definitions for 4 phenotypes of advanced PC: biochemical recurrent (BCR) hormone-naïve nonmetastatic PC, metastatic hormone-naïve advancing PC, nonmetastatic castration-resistant PC (CRPC), and metastatic CRPC. They also discussed treatment advances and offered insights into how improved diagnostics, such as next-generation biological imaging, are affecting treatment decision making.Patients with BCR hormone-naïve nonmetastatic PC have no history of hormonal therapy or androgen deprivation therapy (ADT) and have an increasing PSA level after radical prostatectomy (RP) or radiation therapy (RT) for localized PC. BCR is common, affecting up to 40% of men post RP and up to 50% of men post RT, with most cases occurring within 10 years of treatment.7,8
“Post-RP patients should have a PSA of 0, so any rise in PSA is the signal that there’s BCR, whereas post RT, you really need to reach the nadir, and there are different sets of definitions,” Alec S. Koo, MD, explained. In the United States, the Phoenix criterion is commonly used to determine BCR after RT, with a PSA increase of 2 ng/mL over nadir considered BCR, independent of patients’ hormonal therapy exposure.9
Historically, in patients with BCR, it has been challenging to determine when to conduct imaging studies to establish the location of the recurrence and whether metastasis has occurred. “We all know that at low PSA values, bone scans and CT [computed tomography] scans aren’t necessarily that sensitive to pick up metastatic lesions, so typically you’d wait till it reaches a certain level, but that level is highly variable based on the patient,” Alec Koo said. However, the advent of PC-specific positron emission tomography (PET), particularly fluciclovine F 18 (Axumin) with PET/CT, has shifted this thinking, as it enables detection of sites of recurrence at lower PSA levels than required by conventional imaging modalities. In the BED-001 study, the overall detection rate among 595 patients who received ≥1 injection of fluciclovine for the detection of suspected BCR after RP or RT was 67.7%, with an overall detection rate of 41.4% in patients with a PSA <0.8 ng/mL.10
The ability to diagnose and characterize recurrence earlier enables treatment in this population to be better tailored. The imaging presents "a great opportunity to treat low-volume recurrent disease, either with radiation therapy or possibly surgical extubation, rather than reflexively starting ADT," Neal D. Shore, MD, said, noting that several studies are examining this issue and that a lot of data are forthcoming.
Thus far, results from the FALCON and LOCATE studies have already shown that fluciclovine PET/CT findings can have a significant impact on treatment plans.11,12 In the FALCON trial, 61.2% of men had a change in their treatment plan following fluciclovine PET/CT scanning, with 36.4% of those changes considered major.11 In the LOCATE study, treatment plans were revised for 58.2% of patients, with 77.4% of changes considered major.12 The impact of such treatment changes on outcomes, however, has yet to be determined.
Fluciclovine PET/CT imaging has been approved since 2016 for men with suspected PC recurrence based on elevated PSA levels following prior treatment, and it is currently reimbursed by the Centers for Medicare & Medicaid Services.13 Another agent that is showing considerable promise in clinical trials is gallium-68. “There are reports of detection rates of around 40% to 50% in patients with a PSA level under 0.5 ng/mL,” Phillip J. Koo, MD, said. “We foresee that being the next novel imaging tool that gets FDA approval, and hopefully it will be paid for by our payers as well," he said.The higher Gleason patterns, lack of prior screening, metastatic disease, and hormonal naïve status that typify many patients now entering the clinic have contributed to the recognition of a unique disease state. "[There is potentially] a different biology [from the] sort of the natural progression that we’ve outlined from RP or RT to PSA relapse,” George said. "Recognizing that patients who are de novo coming in the door with metastatic disease may have a more aggressive biology and benefit from early use of combination hormonal therapy and chemotherapy has been a great breakthrough.” He noted that docetaxel and abiraterone acetate (Zytiga) have both shown significant benefit in this population when added to ADT. He proceeded to discuss the CHAARTED, LATITUDE, and STAMPEDE studies, which examined these agents.14-16
In the CHAARTED study, men with metastatic hormone-sensitive PC who received docetaxel in addition to ADT had a 13.6-month longer median overall survival (OS) than those who received ADT alone (57.6 months vs 44.0 months, respectively; HR for death in the combination group, 0.61; 95% CI, 0.47-0.80; P <.001).14 “There was also a longer time to castration resistance and a greater percentage of patients achieving a PSA nadir <0.2 ng/mL. These are all good surrogates to tell us that we’re having a deeper and more durable effect on the tumor than with primary ADT alone,” George explained.
In the LATITUDE study, the addition of abiraterone acetate and prednisone to ADT significantly increased OS and radiographic progression-free survival (PFS) in men with newly diagnosed, metastatic, hormone-sensitive PC.15 The median OS was not reached compared with 34.7 months for those receiving ADT alone (HR for death, 0.62; 95% CI, 0.51-0.76; P <.001). The median length of radiographic PFS was 33.0 months with abiraterone acetate versus 14.8 months with placebo (HR for disease progression or death, 0.47; 95% CI, 0.39-0.55; P <.001).15
In the multiarm STAMPEDE trial, both docetaxel (arm C) and abiraterone acetate (arm G) showed improved OS versus ADT alone (control arm).16 “It was almost uncanny how similar the benefit [with abiraterone acetate] was to docetaxel,” George said.
One key difference between these agents is that docetaxel requires intravenous administration whereas abiraterone acetate is taken orally. With trials showing similar outcomes data, some clinicians might favor abiraterone acetate because of its ease of administration. However, without head-to-head data, clinicians will have to rely on their best clinical judgment. “There’s more work to be done in this space, but it’s no longer acceptable to take a patient with metastatic disease at presentation, particularly extensive disease [>4 metastases at presentation], and treat him with ADT alone,” George said.Nonmetastatic CRPC is considered to have occurred after ADT resistance and upon observation of a PSA increase ≥25% and ≥2 ng/ mL above the nadir, which is confirmed by a second reading 3 or more weeks later, despite a castrate serum testosterone level of ≤50 ng/dL; however the panelists noted that there is some flexibility with this definition.17 “I think in realworld practice most of us would accept that as long as the PSA is going up from nadir and the testosterone-level is <50 ng/dL, then that indeed is CRPC,” Shore said. George explained that there is also some flexibility with the testosterone level. “We see these cases with these slightly higher testosterone levels, where the patients are on an LHRH [luteinizing hormone-releasing hormone agonist], and yet their testosterone is 60 or 65 ng/dL. To me, that’s still CRPC. We draw the line at 50 ng/dL because we must draw the line somewhere, but it’s more of a guideline,” he said, noting that his institution has raised the testosterone threshold to 75 ng/dL in some protocols.
Patients with nonmetastatic CRPC are at high risk of developing metastasis, with 33% of patients developing metastasis within 2 years after CRPC diagnosis, according to a systematic review of >70,000 men with PC who were observed for up to 12 years.18 Therefore, determining when to image to detect metastatic disease is important, and Phillip Koo discussed the Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence Group’s imaging recommendations for these patients. “We recommend a bone scan and CT when patients’ PSA levels reach ≥2 ng/mL, then the next one at 5 ng/mL, and at every doubling of PSA after that based on PSA checks every 3 months,” he said.19
George discussed important markers that signal increased risk of early metastasis. “[Patients with] PSA levels that are >10 ng/mL are at higher risk. [A more rapid] PSA doubling time, particularly PSA doubling times of ≤6 months, indicates a particularly high risk of developing bone metastasis in the next 1 to 2 years. So, looking at those markers, we kind of know who we can sit and watch for a while,” he said. He cautioned that the term nonmetastatic CRPC is a misnomer. “I kind of cringe at this term. Most of these patients have had their prostate out. There is no primary. We know this is metastatic disease. It’s just not radiographic metastatic disease.”
Although the newer biological imaging modalities, such as fluciclovine PET/CT, can detect low-volume metastatic disease, their use has yet to be established in the nonmetastatic CRPC population. “If you look at the label for fluciclovine, it just says elevated PSA following prior therapy. It doesn’t say prior definitive therapy or distinguish the different disease states, so I think [its use in this population] falls under the label,” Phillip Koo said. Although there is no direct evidence to support fluciclovine use in this population, he indicated it might be acceptable to use this imaging modality in the nonmetastatic CRPC space if there is willingness to act on scan results. "If this is a way that you can get a patient into that M1 space officially to start treatment, I think there could be value in that," he said.
The panelists then went on to discuss pivotal findings from 2 phase III clinical trials that subsequently led to FDA approvals for patients with M0 CRPC: the SPARTAN and the PROSPER studies.20, 21
In February, apalutamide (Erleada) became the first treatment approved for patients with nonmetastatic CRPC based on findings from the SPARTAN trial. Apalutamide reduced the risk of metastasis or death by 72% in patients with nonmetastatic CRPC. The median metastasis-free survival (MFS) was 40.5 months in the apalutamide arm versus 16.2 months in the placebo arm (HR, 0.28; 95% CI, 0.23-0.35; P <.0001).
The SPARTAN trial evaluated the safety and efficacy of apalutamide versus placebo in 1207 patients with nonmetastatic CRPC and a rapidly rising PSA level despite receiving continuous ADT. Nonmetastatic status was determined by a negative bone scan, as well as a negative CT of the pelvis, abdomen, chest, and brain. Patients were required to have a PSA doubling time of ≤10 months.
In July, the FDA approved enzalutamide (Xtandi) for nonmetastatic castration-resistant CRPC. The approval is based on the PROSPER trial, in which the combination of enzalutamide and ADT reduced the risk of metastases or death by 71% compared with ADT alone for patients with nonmetastatic CRPC. In the double-blind study, the median MFS was 36.6 months with enzalutamide plus ADT versus 14.7 months with ADT alone (HR, 0.29; 95% CI, 0.24-0.35; P <.0001).
In the trial, 1401 patients with asymptomatic M0 CRPC were randomized to receive ADT plus enzalutamide at 160 mg daily (n = 933) or a matching sugar pill placebo (n = 468). ADT consisted of a gonadotropin- releasing hormone agonist/antagonist. All patients in the study had testosterone levels of ≤50 ng/dL, a PSA doubling time of ≤10 months, and a PSA of ≥2 ng/mL.
“Both of these trials very similarly demonstrated metastasis-free survival in the treatment arm versus the placebo-controlled arms of approximately 2 years, so it is a dramatic change…I think these are dramatically important trials,” said Shore.Patients with metastatic hormone-sensitive PC and those with nonmetastatic CRPC can progress to metastatic CRPC. Historically, metastatic CRPC was considered terminal, with patients' having a median OS of approximately 1 year when treated with traditional chemotherapy.22 However, the advent of many new agents has significantly improved the prognosis in these patients. “The current landscape of therapy includes immunotherapy, traditional taxanes, androgen receptor signaling inhibitors, androgen synthesis inhibitors, and alpha-emitting agents,” Concepcion said.
“[The metastatic CRPC population presents] a great opportunity for us to introduce the idea of genetic profiling,” George said. “For cancers that are stage IV that have gone into the lethal phenotype, about 20% to 25% of tumors will have somatic changes in their DNA damage-repair pathways. BRCA2 and BRCA1 are the most well recognized, but there’s ATM, there’s CHEK2, and there’s Fanconi anemia,” he said. When genes that play a key role in DNA damage repair are identified, the tumors might be susceptible to treatments like poly ADP ribose polymerase (PARP) inhibitors, which prevent DNA repair of cancer cells and lead to cancer cell death. Because it can be difficult to biopsy some metastatic lesions, particularly bone metastases, some PARP inhibitors are being developed with companion diagnostics that profile the tumor by analysis of circulating tumor DNA, George noted.
“There’s one other approach, and that’s to look at the germline,” George said, noting his institution offers this testing even to older patients. “It’s important to recognize the changes we’re looking for are associated with lethal disease, not necessarily associated with the incidence of disease. The genes that are associated with PC incidence are different than the genes that are associated with PC progression and lethality,” he said. “We want to do [germline mutation testing] for patients we would actually treat if they have a genetic predisposition. Germline is not as frequent, but it’s still almost 8% to 10%, so if you send enough [tests out], you’re going to find it,” he explained.
Genetic profiling can open the door to treatments that might not otherwise be under consideration. In one study, 90.8% of patients with incurable solid-tumor malignancies that had progressed on ≥1 prior line of therapy or had no standard first-line treatment options available were found to have ≥1 actionable mutation.23 “It’s not anymore whether you’re African American or you have a family history of PC. It’s all these other ‘hereditary tumors’ that we never thought PC fit into,” Concepcion said. “Hopefully, we will move away from traditional, organ-based cancer treatment to something that’s based more on molecular drivers and what patients’ tumors are expressing,” he said.The understanding of PC has evolved significantly in recent years, and many more treatments have become available for its various phenotypes, which are becoming better understood as imaging modalities and genetic profiling continue to evolve. “Now I can look at a patient and say, ‘There are new medications coming out, and I think we could meaningfully delay your disease onset to metastasis by a couple more years.’ It’s a very exciting time for us as physicians who treat PC,” Alec Koo concluded.