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.”


Continue Reading

“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

  1. Omil-Lima DO, Wu X, Kent MA, et al. Effect of advances in treatment on a population-level of patients with metastatic prostate cancer. J Urol. 2022;(suppl 5):e45. Presented at the American Urological Association 2022 annual meeting. Abstract PD03-10.
  2. George DJ, Sartor O, Miller K, et al. Treatment patterns and outcomes in patients with metastatic castration-resistant prostate cancer in a real-world clinical practice setting in the United States. Clin Genitourin Cancer. 2020;18(4):284-294. doi:10.1016/j.clgc.2019.12.019
  3. Storås AH, Fosså SD, Ursin G, Andreassen BK. Survival trends for patients with primary metastatic prostate cancer before and after the introduction of new antitumor drugs. Prostate Cancer Prostatic Dis. Published September 7, 2021. doi:10.1038/s41391-021-00445-x
  4. George DJ, Sandin R, Agarwal N, et al. Treatment patterns and overall survival (OS) in metastatic castration-sensitive prostate cancer (mCSPC) from 2010 to 2019. Poster presentation at the European Association for Medical Oncology 2022 Congress. Poster 1384P.
  5. Kim IE, Jang TL, Kim S, et al. Marginal improvement in survival among patients diagnosed with metastatic prostate cancer in the second-line antiandrogen therapy era. Cancer Med. 2021;10:7909-7920. doi:10.1002/cam4.4074
  6. Desai MM, Cacciamani GE, Gill K, et al. Trends in incidence of metastatic prostate cancer in the US. JAMA Netw Open. 2022;5(3):e222246. doi:10.1001/jamanetworkopen.2022.22
  7. Gallicchio L, Devasia TP, Tonorezos E, et al. Estimation of the numbers of individuals living with metastatic cancer in the United States. J Natl Cancer Inst. Published online August 22, 2022. doi:10.1093/jnci/djac158
  8. Shore ND, Renzulli J, Fleshner NE, et al. Active surveillance plus enzalutamide monotherapy vs active surveillance alone in patients with low-risk or intermediate-risk localized prostate cancer. JAMA Oncol. 2022;8(8):1128-1136. doi:10.1001/jamaoncol.2022.1641
  9. Weiner AB, Ko OS, Li EV, et al. Survival following upfront chemotherapy for treatment-naïve metastatic prostate cancer: a real-world retrospective cohort study. Prostate Cancer Prostatic Dis. 2021;24:261-267. doi:10.1038/s41391-020-00278-0
  10. Sartor O, la Fourgère C, Essler M, et al. 177Lu-Prostate-specific membrane antigen ligand after 223Ra treatment in men with bone-metastatic castration-resistant prostate cancer: Real-world clinical experience. J Nucl Med. 2022;63:410-414. doi:10.2967/jnumed.121.262240
  11. Ost P, Reynders D, Decaestecker K, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: A prospective, randomized, multicenter phase II trial. J Clin Oncol. 2017;36:446-453. doi:10.1200/JCO.2017.75.4853
  12. Deek MP, van der Eecken, K, et al. Long-term outcomes and genetic predictors of response to metastasis-directed therapy versus observation in oligometastatic prostate cancer: Analysis of STOMP and ORIOLE trials. J Clin Oncol. Published online August 24, 2022. doi:10.1200/JCO.22.00644
  13. Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. Eur Urol. 2014;65:1058-1066. doi:10.1016/j.eururo.2013.11.012
  14. Elmehrath AO, Afifi AM, Al-Husseini MJ, et al. Causes of death among patients with metastatic prostate cancer in the US from 2000 to 2016. JAMA Netw Open. 2021;4(8):e2119568. doi:10.1001/jamanetworkopen.2021.19568
  15. Attard G, Murphy L, Clarke NW, et al. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. Lancet. 2022 Jan 29;399(10323):447-460. doi:10.1016/S0140-6736(21)02437-5

This article originally appeared on Renal and Urology News