Delaying Progression Amidst the Biologic Heterogeneity of Castration-Resistant Prostate Cancer
Our expert panel members discuss the impact of biologic heterogeneity on disease progression, treatment selection, and outcomes in patients with castration-resistant prostate cancer (CRPC).
Q: How does the biologic heterogeneity of CRPC influence decisions about treatment?
Chief, Division of Hematology and Medical Oncology
“Identifying patients with uncommon—but important—genetic signatures can lead to dramatic responses to a drug that might not work in patients without these mutations.”
Delaying metastases by 2 years in those with nonmetastatic CRPC (nmCRPC) and a rapid prostate-specific antigen (PSA) doubling time is clinically meaningful for a variety of reasons, one of which being that, despite earlier treatment and all of our efforts, we are still unable to cure metastatic prostate cancer. These cancers are not a single clone and are very heterogeneous, and that heterogeneity reflects different biologies that seem to lead to not only castration resistance, but also the various subclones of cancer cells that may differ from patient to patient. We now know that there may be different types of cancer cells in a single patient with prostate cancer, and these cells may express different genetic abnormalities that drive subsets of cancers in different ways. One example is the poorly differentiated aggressive variant prostate cancer (AVPC; formally referred to as anaplastic prostate cancer). In most cases, prostate cancer development and progression are dependent on androgen receptor (AR) signaling. This is true even in the castration-resistant setting, which may be targeted by second-generation hormonal therapy. However, in a subset of patients with AVPC, the disease is characterized by androgen-independent cancer biology, short-term response to hormonal treatment, and typically early and extensive visceral metastases, low PSA levels, and poor outcomes. We believe that disease progression in this group may sometimes be driven by mutations in the DNA damage repair pathway involving BRCA2, either as a germline or somatic mutation. Why is this important? Well, 20% or more of prostate cancer metastases harbor DNA damage repair defects, and subsets with AVPC may respond favorably to platinum-based chemotherapy or PARP inhibition. Identifying patients with uncommon—but important—genetic signatures can lead to dramatic responses to a drug that might not work in patients without these mutations.
C. E. and Bernadine Laborde Professor of Cancer Research
“The heterogeneity of CRPC is potentially exploitable with selected therapies. This is a part of the future that will be here almost before we know it.”
One thing that is increasingly intriguing to me is the ability to track this heterogeneity over time, with things such as circulating tumor DNA and even repetitive biopsies. We are seeing that the heterogeneity of CRPC is potentially exploitable with selected therapies. This is a part of the future that will be here almost before we know it. For instance, therapeutic compounds targeting the PI3K/Akt/mTOR signaling pathway are being tested in clinical trials for patients with metastatic CRPC. One way to address the heterogeneity of this disease is to target the cells with different types of treatments. Dr Oh and I were relatively early adopters of platinum-based regimens, which are highly active in patients with select DNA repair mutations, particularly BRCA1/2. We are currently using circulating tumor DNA analysis and screening greater numbers of patients for germline abnormalities and hereditary cancers. We have found that a family history of breast or ovarian cancer is actually more informative than a family history of prostate cancer in this regard. As relates to the heterogeneity of AR signaling abnormalities, when you look at the underlying mutation patterns in CRPC, you begin to realize that the AR splice variant-7 (AR-V7) is only 1 of several potential AR abnormalities. I have never personally ordered a test for the AR-V7. Moreover, in my opinion, therapeutic layering with multiple AR-targeted agents (eg, adding darolutamide to enzalutamide) is unlikely to yield substantially improved outcomes in this setting. There are some preliminary data suggesting that darolutamide blocks the activity of certain mutant ARs that arise in response to anti-androgen therapies, but we need more definitive data before we can say that this might be an exploitable attribute.
Ken and Donna Derr – Chevron Distinguished Professor
“The fact that you can have a biopsy-proven metastatic site that had remained quiescent for many years and subsequently became more active is intriguing.”
This is an area that is being revolutionized by advanced imaging and new forms of molecular characterization, including analyses of circulating tumor cells and cell-free DNA. It is remarkable to me that sometimes we see patients who were treated with surgery and/or radiation for what was believed to be localized disease, they may have had an undetectable PSA for 7 or 8 years, and then, all of a sudden, they are found to have metastases, frequently in unusual locations such as the lungs, paratracheal region, or supraclavicular lymph nodes. The fact that you can have a biopsy-proven metastatic site that had remained quiescent for many years and subsequently became more active is intriguing. We and others are characterizing tissue samples from these patients in an effort to identify possible molecular correlates of these advanced lesions. There is no question in my mind that advanced imaging such as prostate-specific membrane antigen–positron emission tomography identifies disease much more effectively than conventional imaging. Now the question is, how does this translate to oncologic benefit? Our approach to treating patients with nmCRPC is changing quite rapidly. We can identify patients who are at greater risk for metastatic disease (ie, high-volume disease, high-risk cancer, early recurrence, rapid PSA doubling time). Some CRPC variants evade therapy through a mechanism whereby the tumors become less dependent on AR signaling; neuroendocrine prostate cancer should be suspected in patients who progress in the setting of low- or moderately rising PSA levels that suggest a less AR-driven disease. The use of molecular biomarkers and advanced imaging to identify emerging variants and improve patient selection for therapy is an area of active investigation, and it promises to deliver big changes over the next 10 years.
Li Q, Deng Q, Chao HP, et al. Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses. Nat Commun. 2018;9(1):3600.
Moilanen AM, Riikonen R, Oksala R, et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep. 2015;5:12007.
Nicolosi P, Ledet E, Yang S, et al. Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines. JAMA Oncol. 2019;5(4):523-528.
Nyberg T, Frost D, Barrowdale D, et al. Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Eur Urol. 2019 Sep 5. pii: S0302-2838(19)30675-X. doi: 10.1016/j.eururo.2019.08.025. [Epub ahead of print]
Pomerantz MM, Spisák S, Jia L, et al. The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer. 2017;123(18):3532-3539.
Vlachostergios PJ, Puca L, Beltran H. Emerging variants of castration-resistant prostate cancer. Curr Oncol Rep. 2017;19(5):32.