Metastatic Prostate Cancer: Investigators Ponder New Path to Improve Survival

Novel therapies that have entered clinical practice over the past 12 years have extended the lives of men with metastatic prostate cancer, population-based studies show. Still, survival gains have been modest, and the prognosis for men with metastatic prostate cancer remains poor. Investigators involved in prostate cancer research say longer survival is possible, but the management approach to metastatic prostate cancer, which is on the rise in the United States, needs to change. Based on insight gained from ongoing research and the availability of more precise imaging techniques, they believe the path forward should involve earlier use of aggressive treatment.

“I am convinced that treating early and hard is better than late and less,” said urologic oncologist Judd W. Moul, MD, the James H. Semans Distinguished Professor of Urologic Surgery at Duke University School of Medicine in Durham, North Carolina, who has been extensively involved with clinical trials of prostate cancer therapies. “Some doctors still ‘hold the good stuff in their back pocket’ and avoid or delay the most effective options up front.” 

“Starting multiple therapies earlier in the disease course seems to provide the most benefit,” said prostate cancer investigator Jonathan E. Shoag, MD, Associate Professor of Urology at University Hospitals Cleveland Medical Center and Case Western Reserve University, both in Cleveland, Ohio.

Despite all of the scientific advancements, metastatic prostate cancer “is still a bad disease,” Dr Shoag said. “The goal should be preventing cancer from becoming metastatic in the first place. We can do this by screening, diagnosing, and intervening in the disease course earlier.”

Advanced molecular imaging, such as positron emission tomography (PET), should be used to identify metastasis as early as possible, before it spreads to distant anatomic sites, according to investigators. Potent treatments should be considered at this stage. Physicians also should try to delay development of both metastasis and castration-resistant prostate cancer (CRPC), which clinical trial data suggest is possible.

Earlier identification and treatment of metastatic CRPC (mCRPC) is key, Dr Moul said, adding that targeted therapy based on the molecular characteristics of the patient or tumor or both continues to lead to advancements in treatment. “I remain optimistic that we will continue to achieve better survival with targeted combos and with further molecular discoveries,” Dr Moul said. 

Advances in PET imaging, such as PSMA (prostate-specific membrane antigen) PET, that improve detection of metastases compared with traditional bone scans, computed tomography (CT), and magnetic resonance imaging (MRI) will play an increasingly important role, Dr Moul said. “As we all know, traditional bone scans and CT/MRI miss a lot of early metastatic disease,” he said. “Novel functional imaging with PET is opening a whole new era. At this point, I routinely order PSMA PET to work up biochemical recurrence as well as in nonmetastatic CRPC and in newly diagnosed men with very high risk disease.”

Radiation oncologist Amar U. Kishan, MD, Chief of the Genitourinary Oncology Service and Vice Chair of Clinical and Translational Research for the Department of Radiation Oncology at the University of California, Los Angeles, also embraces PSMA PET. “I believe that PSMA scans should be routine as part of the diagnostic workup for patients with recurrent disease after primary therapy, and even for those with previous recurrence who have a second recurrence and those who might have progression on therapy,” Dr Kishan said. “While there are certain rarer types of prostate cancer that might not be detectable on PSMA PET/CT, PSMA PET has been shown to greatly increase sensitivity and even specificity for disease over older forms of imaging.”

Urologist Stephen J. Freedland, MD, Director of the Center for Integrated Research in Cancer and Lifestyle at Cedars-Sinai Medical Center in Los Angeles, California, observed that the aggressive management of metastatic disease imaged with conventional modalities (bone scan or CT) has pushed survival out to 5 or 6 years. “Finding cancers even earlier will create a lead-time bias and thus survival from that alone with be longer,” said Dr Freedland, who also is the Warschaw Robertson Law Families Chair in Prostate Cancer. “However, whether the same therapies applied to PET-only metastases extends survival even longer is unknown.”

For now, the most promising treatments are the novel hormonal therapies, according to Dr Freedland. “They have shown remarkable benefits across multiple disease states, including in castration-sensitive disease to prevent development of CRPC,” he said, adding that, relatively speaking, the drugs are well tolerated despite their side effects.

“For sure, the future will include targeted molecular therapies,” Dr Freedland said. “We are there now with PARP inhibitors for some patients.”

The Expanding Armamentarium

Patients with metastatic prostate cancer in the United States have benefited from an expanding armamentarium of novel therapies, especially since 2010, when the Food and Drug Administration (FDA) approved cabazitaxel for mCRPC and sipuleucel-T, the first therapeutic cancer vaccine, for asymptomatic or minimally symptomatic mCRPC. These approvals were followed by the approval of abiraterone in 2011 and enzalutamide in 2012 for treating mCRPC. The following year, FDA approved the radiopharmaceutical radium-223 for the treatment of symptomatic bone metastases in CRPC. In 2018 and 2019, the FDA approved apalutamide and darolutamide, respectively, for treating nonmetastatic CRPC, but subsequently expanded the indication for these agents, as well as for abiraterone and enzalutamide, to include metastatic castration-sensitive prostate cancer (mCSPC). The FDA in 2022 approved lutetium-177 PSMA, another radiopharmaceutical, for treating patients who have mCRPC and PET scans demonstrating PSMA uptake in their metastases.

Prolonged Survival

Real-world evidence shows that the newer agents are improving overall survival of men who have metastatic prostate cancer, a confirmation of clinical trial data. At the American Urological Association’s 2022 annual meeting, Dr Shoag and colleagues presented findings from their study of Surveillance, Epidemiology, and End Results (SEER) program data showing that men diagnosed after 2011 (the year the FDA approved abiraterone) had a significant 20% lower risk for all-cause mortality and 25% lower risk for prostate cancer-specific mortality, respectively, compared with those diagnosed from 2000 to 2008.¹ In addition, an analysis of data from the electronic medical records of 2559 men with mCRPC showed that the median overall survival of patients who received at least 1 line of abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, or radium-223 had a significantly longer median overall survival compared with those who did not (23.7 vs 10.1 months), investigators reported in Clinical Genitourinary Cancer.² And a Norwegian study published in Prostate Cancer & Prostatic Diseases demonstrated that the median overall survival of men with mCRPC increased from 2.3 years in 2004-2009 to 3.3 years in 2015-2018. The 3-year overall survival rate increased to 51% from 41% between those time points.³

Overall survival also improved among men with mCSPC after the introduction of docetaxel and novel hormonal therapies (abiraterone, enzalutamide, apalutamide) for treating that disease state, according to study findings presented at the European Society for Medical Oncology 2022 Congress. Daniel J. George, MD, of Duke University Medical Center in Durham, North Carolina, and colleagues studied 39,292 men with mCSPC (33,641 with Medicare coverage and 5651 receiving care at Veterans Affairs [VA] medical facilities). The investigators divided patients into 3 cohorts of patients who received first-line treatment for mCSPC: those treated in 2010 to 2011 (prior to the introduction of novel hormonal therapies for mCRPC); 2012 to 2014 (to reflect the introduction of novel hormonal therapies for mCRPC); and 2015 to 2018 (for Medicare patients) and 2015 to 2019 (for VA patients) to reflect the introduction of novel hormonal therapies and docetaxel for treating mCSPC. Compared with Medicare and VA patients treated during 2010 to 2011, Medicare patients treated from 2015 to 2018 and VA patients treated from 2015 to 2019 had a significant 13% and 15% lower risk for death, respectively, the investigators reported.⁴

Despite the positive trend, however, improvements in survival have been marginal, according to the findings of a population-based study published in Cancer Medicine.⁵ In an analysis of SEER data, a team led by Isaac Yi Kim, MD, of Rutgers Cancer Institute of New Jersey in New Brunswick, found that the median survival time increased from 24 months for men diagnosed with metastatic prostate cancer from 2000 to 2003 to 28 months for those diagnosed with it from 2010 to 2016.

“Although we have made considerable headway in the options available to patients with advanced prostate cancer, we still are likely seeing advancements provide additional months, rather than years, in terms of overall survival,” said prostate cancer investigator Christopher P. Filson, MD, Associate Professor of Urology at Emory University School of Medicine in Atlanta, Georgia, where he is a member of the Cancer Prevention and Control research program at the Winship Cancer Institute. “The median survival for men presenting with metastatic disease is still around 3 years, so there is still room for improvement before we consider this a chronic disease state for most advanced prostate cancer patients.”

Dr Filson also observed, “As of right now there is a limit to what we can achieve with medications and systemic therapies for patients with metastatic prostate cancer. To date, cure in that state is not possible. However, I remain hopeful that continued scientific advancements can help reach the goal of eventually offering curative options for patients with metastatic prostate cancer. For now, the best path to minimizing the detrimental effects of prostate cancer is to promote early detection and judiciously offering curative treatment to those who need it most.”

Still, the growing list of effective treatments is good news given that metastatic prostate cancer is on the rise in the United States. In a study of SEER data, Mihir M. Desai, MD, MPH, of University of Southern California’s Keck School of Medicine in Los Angeles, and colleagues found no statistically significant increase in the incidence of metastatic prostate cancer from 2004 to 2010 among men aged 45 to 75 years, but the incidence increased 41% from 2010 to 2018, according to findings published in JAMA Network Open.⁶ Among men aged 75 years or older, the incidence declined during 2004 through 2011, but rose 43% afterward, according to the investigators. They pointed out that the upward trend occurred following US Preventive Services Task Force recommendations against routine PSA screening, first for men older than 75 years in 2008 and then for all men in 2012. Based on a separate analysis of SEER data, investigators at the National Cancer Institute led by Lisa Gallicchio, PhD, project that the number of men living with metastatic prostate cancer in the United States will rise to 156,812 by January 1, 2025, up from an estimated 120,368 men on January 1, 2018, according to a recent report in the Journal of the National Cancer Institute.⁷

Prostate cancer care already is moving toward earlier use of newer agents, as the FDA approvals of abiraterone, enzalutamide, apalutamide, and darolutamide for use in mCSPC suggest. Some investigators have considered the use of novel agents even earlier. For example, Neal D. Shore, MD, of Carolina Urologic Research Center in Myrtle Beach, South Carolina, and collaborators tested the use of enzalutamide in patients on active surveillance for localized prostate cancer. Compared with patients undergoing active surveillance alone, those who also received enzalutamide experienced significant 46% lower risk of prostate cancer progression and 29% lower risk of PSA progression, the investigators reported in JAMA Oncology. The enzalutamide arm also was 3.5 times more likely to have a negative biopsy result.⁸

Dr Moul observed that physicians are underusing effective therapies for men with mCSPC. Despite having 5 therapeutic agents (docetaxel, abiraterone, apalutamide, darolutamide, and enzalutamide) that markedly improve survival over androgen deprivation therapy (ADT) alone in men with mCSPC, “too many men in 2022 are still getting ADT alone,” Dr Moul said, adding that urologists need to recognize that ADT alone is substandard care for most men with mCSPC.

Transformation Into a Chronic Illness?

Adam B. Weiner, MD, a urologic oncology fellow at the University of California, Los Angeles, said recent evidence suggests that investigators are making strides in turning metastatic prostate cancer into a chronic illness. He pointed to the ARASENS trial, which examined the effect of ADT plus docetaxel, with or without darolutamide, on survival in men with mCSPC. At the end of follow-up, median survival was more than 4 years among the men who did not receive darolutamide but never reached among the men who received the drug. In addition, the median time to castration resistance was 19 months among the men who did not receive darolutamide and never reached among the men who did receivedarolutamide.

“I think we still have a lot to learn about treatments for metastatic prostate cancer, and I think there is still room to grow,” Dr Weiner said. “First, we will still start to see the benefit of more targeted therapies for individual patients. We’ll continue to see newer agents targeting patients with specific susceptibilities based on genomic alterations or certain gene expression patterns. We will also continue to learn about the optimal ordering of treatments for patients who receive more than 1 line of medication for castration-resistant prostate cancer. I also think the treatments we are optimizing for men with hormone-sensitive prostate cancer will continue to delay the onset of castration resistance.”

“Triplet therapy” in the form of ADT, docetaxel, and an androgen receptor antagonist “is the most interesting strategy right now,” Dr Weiner said, adding this approach would be particularly beneficial for patients with a high-volume burden of metastatic cancer.

The ARASENS trial showed significant improvement in overall survival when darolutamide was added to docetaxel and ADT and delayed the need for additional treatments. For patients with low-volume metastatic prostate cancer, there is no direct evidence to support one treatment over another at this point, he said.

An important consideration, he said, is the use of androgen receptor antagonists in patients with high-risk nonmetastatic prostate cancer. Moving up the use of these agents can delay onset of metastatic disease, as demonstrated in an analysis of data from the STAMPEDE trial published in the Lancet. Patients with high-risk nonmetastatic prostate cancer who received enzalutamide in addition to abiraterone plus prednisolone had superior metastasis-free survival at 6 years compared with those who did not (82% vs 69%).¹⁵

Upfront Chemotherapy

Some research suggests that there may be a place for upfront chemotherapy. Dr Weiner led a real-world study comparing upfront chemotherapy in patients with de novo mCSPC (within 4 months of diagnosis) with a control group of patients who received no chemotherapy or chemotherapy later than 12 months after diagnosis. The median follow-up duration was 23 months. The median overall survival was significantly higher in the upfront chemotherapy group compared with the control arm (35.7 vs 32.5 months), which corresponded to a significant 22% lower risk for death, Dr Weiner’s team reported in Prostate Cancer & Prostatic Diseases.⁹

Radiopharmaceutical Sequencing 

In a small real-world study, Oliver Sartor, MD, of Tulane University School of Medicine in New Orleans, Louisiana, and collaborators examined the use of lutetium-177 PSMA following radium-223 for bone-metastatic CRPC. Patients received radium-223 (an alpha particle emitter) for a median of 6 injections and subsequent lutetium-177 PSMA (a beta particle emitter) for a median of 3.5 months. The median time between the treatments was 8 months. The median overall survival was 28 months from the start of radium-223 and 13.2 months from the start of lutetium-177 PSMA, the investigators reported in the Journal of Nuclear Medicine.¹⁰ The authors acknowledged that their small sample size precludes definitive conclusions, but noted that their data, especially related to the duration of lutetium-177 PSMA, suggest that the use of this medication after radium-223 is feasible in a real-world setting.

Metastasis-Directed Therapy

Meanwhile, metastasis-directed therapy (MDT) is emerging as a treatment option for men with low-volume metastases, a trend helped along by highly sensitive and specific molecular imaging techniques that can identify metastases early. In a prospective randomized phase 2 trial that enrolled men with oligometastatic prostate cancer, Piet Ost, MD, PhD, of Ghent University Hospital in Belgium, and colleagues demonstrated that the median ADT-free survival was 21 months for men who had MDT and 13 months for those who underwent surveillance, the investigators reported in the Journal of Clinical Oncology.¹¹ The study population had a median follow-up duration of 3 years.

Further, in an analysis of pooled data from the prospective STOMP and ORIOLE trials, a team led by Phuoc T. Tran, MD, PhD, of the University of Maryland School of Medicine in Baltimore, found that MDT was significantly associated with a 56% reduction in the risk of disease progression in men with oligometastatic CSPC compared with observation after a median follow-up of 52 months. The median PFS — the study’s primary endpoint — was 11.9 months with MDT compared with 5.9 months with observation, Dr Tran and colleagues reported in the Journal of Clinical Oncology.¹² Among patients with high-risk mutations, MDT was significantly associated with a 95% lower risk for disease progression, compared with observation, according to the investigators. The median PFS was 7.5 months among MDT recipients compared with 2.8 months among those who underwent observation. Looking only at the MDT cohort, the investigators found that patients without high-risk mutations had a significantly longer median PFS compared with those who had these mutations (13.4 vs 7.5 months).

Treatment of Primary Tumor 

Another approach that may prolong life is treatment of the primary prostate tumor. Stephen H. Culp, MD, of the University of Virginia in Charlottesville, and colleagues conducted a population-based study that included 8185 men with metastatic prostate cancer at diagnosis identified using SEER data: 7811 patients who received no surgery or radiation therapy (NSR), 245 who underwent RP, and 129 who received brachytherapy. The 5-year overall survival rates were significantly higher for the RP and brachytherapy groups (67.4% and 52.6%, respectively) compared with the NSR group (22.5%), according to data published in European Urology.¹³ The predicted disease-specific survival rates also were higher for the RP and brachytherapy arms compared with the NSR group (75.8% and 61.3% vs 48.7%, respectively).

Death From Other Causes

Treatments that prolong the lives of men with metastatic prostate cancer could mean increasing the likelihood of dying from something else. In a retrospective cohort study using 2000 to 2016 SEER data, investigators led by Omar Alhalabi, MD, of The University of Texas MD Anderson Cancer Center in Houston, found that among patients who died within 2 years of their diagnosis of metastatic prostate cancer, 79.0% died from their cancer while 15.7% died from noncancer causes such as cardiovascular disease and 5.3% died from other cancers, according to findings published in JAMA Network Open.¹⁴ But among those who died more than 5 years after their diagnosis, the proportion of patients dying from prostate cancer declined to 66.6% and the proportion of those dying from noncancer causes or other cancers increased to 25.4% and 8.0%, respectively.

The American Cancer Society estimates that 34,500 men in the United States will die from prostate cancer in 2022. Although metastatic prostate cancer remains incurable despite the best that state-of-the-art medical science has to offer, the therapeutics and imaging techniques now available, as well as encouraging developments on the horizon, offer the promise of reducing that number in the years ahead.

References

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