expert roundtables

Active Areas of Research in the Treatment of Prostate Cancer

by Leonard Gomella, MD; and Daniel P. Petrylak, MD

Overview

Prostate cancer treatment is entering the molecular/genomic era. The risk stratification of patients with germline mutations in BRCA1/2 is now viewed as an important step, and other potentially targetable genomic alterations are being pursued. Intense research efforts are focused on the optimal sequencing of available therapies, including next-generation androgen receptor (AR)–directed therapies, chemotherapy, and targeted agents.

Q:

What are some of the important research questions and active areas of investigation in the field right now?

Daniel P. Petrylak, MD

Professor of Medicine (Medical Oncology) and Urology
Codirector, Signal Transduction Research Program
Yale Cancer Center
Yale School of Medicine
New Haven, CT

“One area of substantial research interest involves the next-generation AR-directed therapies and the sequencing of these agents with chemotherapy in patients with mCRPC.” 

Daniel P. Petrylak, MD

We are currently entering the molecular era for prostate cancer. We have been behind other sites such as lung cancer, which really has been a model for the development of genomically targeted therapy. However, we now know that patients with prostate cancer who have germline mutations in the BRCA2 tumor suppressor are at increased risk of developing prostate cancer and of developing aggressive disease; they have worse clinical outcomes than noncarriers when treated with surgery or radiotherapy. Based on these findings, we are beginning to stratify and treat patients accordingly.

Another area of substantial research interest involves the next-generation AR-directed therapies and the sequencing of these agents with chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC). In the CARD trial, patients with mCRPC who previously received docetaxel and 1 of 2 AR inhibitors (ie, either abiraterone or enzalutamide) were randomized to cabazitaxel 25 mg/m2  plus prednisone and granulocyte colony-stimulating factor or the other AR inhibitor. The results of this study demonstrated a significant improvement in progression-free survival and overall survival in those who received cabazitaxel. However, it has been noted that the average patient in the CARD trial may not be the average patient with mCRPC. The trial demographics were suggestive of a population with more aggressive disease at baseline and more hormonally insensitive disease than is typical. There was a requirement for disease progression within 12 months of initiation with abiraterone or enzalutamide. All of this underscores the importance of considering the individual patient. The patient’s age, performance status, and how you expect them to do with treatment all need to be factored in. I think that, in the final analysis, if you have a scenario in which the outcomes with 2 different treatments will likely be about the same, a key question becomes: What side effects are they willing to put up with? Additionally, even when a treatment shows a clear survival advantage, one needs to view those trial data from the perspective of the individual patient and his comorbidities and status at baseline.

The best ways to treat patients who have a low metastatic burden is another important area of research. Data from the STAMPEDE trial showed that, among men with newly diagnosed metastatic disease, those with a low metastatic burden benefit from radiotherapy to the primary tumor. 

Leonard Gomella, MD

Chairman, Department of Urology
Bernard W. Godwin, Jr. Professor of Prostate Cancer
Sidney Kimmel Medical College
Sidney Kimmel Cancer Center
Thomas Jefferson University
Philadelphia, PA

“Another very active area is the optimal treatment approach for patients with clinically localized, high-risk prostate cancer. Numerous ongoing trials are investigating neoadjuvant and adjuvant systemic therapies for patients with high-risk disease using previously approved and novel agents.”

Leonard Gomella, MD

I agree that we are entering a new more molecular, more genomic phase right now. If you consider BRCA abnormalities, this applies to a minority of men with prostate cancer, but what we are coming to appreciate is that these are the men who need our focus. These are the patients who, if identified early, are likely to develop a problem with aggressive disease. Most of the work with the PARP inhibitors has been done in late-stage mCRPC, where the drug approvals take place, but we are all working very intently on early stage disease, attempting to determine which men should undergo genetic testing and implications for screening. It is well established now, mainly from the hereditary breast and ovarian cancer literature, that male relatives of women with these hereditary abnormalities should be tested for BRCA1/2 mutation. Thus, genetic testing could help identify those patients who would be candidates for either active surveillance or treatment. In late-stage disease, the use of PARP inhibition alone is now available for men with these specific DNA repair pathway abnormalities. Combining PARP inhibitors with other systemic therapies is also being explored.

Another very active area is the optimal treatment approach for patients with clinically localized, high-risk prostate cancer. Numerous ongoing trials are investigating neoadjuvant and adjuvant systemic therapies for patients with high-risk disease using previously approved and novel agents.

Finally, I think that it is important to acknowledge all of the research that has allowed active surveillance in localized prostate cancer to become more mainstream. Approximately 15 years ago, patients would have a biopsy and, if positive, would then be treated with definitive surgery or radiation. Today, nearly half of the patients we treat are being monitored on various active surveillance protocols. We are getting better at taking the pathological features of a patient’s newly diagnosed localized prostate cancer, incorporating molecular analyses, and gaining insights into the likelihood of progression.

References

Baumgart SJ, Nevedomskaya E, Lesche R, Newman R, Mumberg D, Haendler B. Darolutamide antagonizes androgen signaling by blocking enhancer and super-enhancer activation. Mol Oncol. 2020 Apr 24. doi:10.1002/1878-0261.12693

de Wit R, de Bono J, Sternberg CN, et al; CARD Investigators. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206

Gillessen S, Attard G, Beer TM, et al. Management of patients with advanced prostate cancer: report of the Advanced Prostate Cancer Consensus Conference 2019. Eur Urol. 2020;77(4):508-547. doi:10.1016/j.eururo.2020.01.012

Giri VN, Hyatt C, Gomella LG. Germline testing for men with prostate cancer: navigating an expanding new world of genetic evaluation for precision therapy and precision management. J Clin Oncol. 2019;37(17):1455-1459. doi:10.1200/JCO.18.02181

Mateo J, Porta N, Bianchini D, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21(1):162-174. doi:https://doi.org/10.1016/S1470-2045(19)30684-9

Parker CC, James ND, Brawley CD, et al; STAMPEDE Investigators. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366. doi:10.1016/S0140-6736(18)32486-3

Taylor RA, Fraser M, Rebello RJ, et al. The influence of BRCA2 mutation on localized prostate cancer. Nat Rev Urol. 2019;16(5):281-290. doi:10.1038/s41585-019-0164-8

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