The treatment landscape in prostate cancer continues to improve with the continued development of novel drug classes and therapeutics, such as oral androgen signaling receptor inhibitors and darolutamide (Nubequa) in combination with docetaxel, Reichert begins. Despite this wealth of options, uncertainty remains regarding how to identify the optimal candidates for a given approach, Reichert says.

To address this knowledge gap, research in early-stage metastatic hormone-sensitive prostate cancer is focused on the predictive value of clinical features such as disease distribution, Reichert states, as well as biomarkers like circulating tumor DNA, circulating tumor cells, and the RNA sequence. Many patients in clinic do not experience responses with intensified doublet and triplet regimens despite their efficacy in a clinical trial setting, he notes. As such, it is vital to pinpoint patients with high-risk features early in the treatment course, Reichert says. This allows patients to gain a more accurate understanding of their disease prognosis, receive the most beneficial standard regimen, and potentially be directed towards clinical trials targeting difficult-to-treat pathways, Reichert explains.

In addition, clinical trials in prostate cancer may also be designed to address questions regarding lineage plasticity. This includes how to exploit key pathways and proteins involved in this clinical phenomenon, how to determine when patients' disease transitions to a more aggressive variant, and whether to focus on them prior to or following this shift, Reichert details. Another intriguing research topic is the viability of utilizing bipolar testosterone to undo the epigenetic reprogramming responsible for lineage plasticity, he adds. Individual institutions will have to determine which questions to focus on, although all are important and promising avenues for future collaboration, Reichert concludes.

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Zachery Roger Reichert, MD, PhD, discusses key research questions to explore in early-stage prostate cancer.

Dr Reichert on Key Research Questions in Prostate Cancer

Zachery Roger Reichert, MD, PhD, clinical associate professor, Internal Medicine, Hematology/Oncology, the University of Michigan Rogel Cancer Center, discusses the effects novel agents and pathways have had on the treatment of patients with prostate cancer.

Understanding how to match the biology of a patient’s individual prostate cancer with their overall disease type is important, Reichert begins. Additionally, it is imperative to design clinical trials that help researchers learn as much as possible about the biology of the investigational therapies to then determine the patients who are most likely to benefit from a specific treatment, he explains. For instance, treating every patient with prostate cancer with docetaxel (Taxotere) with no upfront consideration of which patients are most likely to benefit from this approach is now an outdated strategy, Reichert emphasizes.

Research efforts are revealing more about the known heterogeneity of prostate cancer. The heterogeneity of this disease allows some patients to live for 10 years with a hormone therapy alone, while causing others to progress within 6 months, he expands. Now that researchers can interrogate prostate cancer heterogeneity by evaluating mutations and gene rearrangements, these abilities open new investigational avenues, Reichert adds. All these mutations and rearrangements typically work through the pathways of RNA expression, protein expression, protein half-lives, and epigenetic regulation. Therefore, Reichert believes that descriptions of prostate cancer biology have been limited by the technology to describe that biology.

More advanced technology can help determine which patients will benefit the most from targeted therapies, Reichert continues. For example, PARP inhibitor decision making has evolved over the past few years, Reichert says. Although researchers have determined some of the patients who are likely to benefit from PARP inhibitors, stratifying patient populations into smaller groups and integrating data may reveal additional cohorts that can show which patients are truly benefiting from these therapies, he concludes.

Zachery Roger Reichert, MD, PhD, discusses the effects novel agents and pathways have had on the treatment of patients with prostate cancer.


Dr Reichert on Investigating Novel Agents and Pathways in Prostate Cancer

Zachery Roger Reichert, MD, PhD, clinical associate professor, Internal Medicine, Hematology/Oncology, the University of Michigan Rogel Cancer Center, discusses novel agents and pathways under exploration in prostate cancer.

Although many pathways are being explored in prostate cancer, questions remain regarding the pathways that should be targeted, Reichert begins. In an 

® State of the Science Summit™, Reichert and colleagues from the Rogel Cancer Center each gave presentations on topics spanning genitourinary cancer treatment. In his presentation, Reichert provided updates on pathways involved in lineage plasticity, a clinical phenomenon that is becoming increasingly common as variants of prostate cancer arise that are not dependent on androgen receptors. Thus, in many patients with prostate cancer, therapies geared toward the androgen receptor are not effective, and additional therapies for these patients are needed, he emphasizes. Reichert says that although oncologists are finding better ways to identify these patients, the best treatment strategies for this population have yet to be determined.

JAK/STAT inhibitors are available for patients with prostate cancer, and more are under investigation, as well astherapies targeting DLL3, another protein involved in lineage plasticity, Reichert expands. Notably, a host of other epigenetic and immune modulating drugs are also being explored, he says. These patients may also respond to immunotherapy, which has always been a holy grail for prostate cancer, Reichert emphasizes. Moreover, PSA remains an exciting pathway, especially with the 2022 FDA approval of Lutetium Lu 177 vipivotide tetraxetan (Pluvicto) in patients with prostate-specific membrane antigen (PSMA)–positive metastatic castration-resistant prostate cancer. This agent is the first of multiple different PSMA-directed therapies that may gain approval, Reichert adds.

Moreover, antibody-drug conjugates and small molecules targeting PSMA are also entering the prostate cancer treatment landscape, Reichert says. The entire PSMA pathway may be exploited in different ways, which may become an issue, Reichert warns. If more than 1 available agent targets a certain pathway, optimal treatment sequencing with these agents will need to be defined, and combination regimens may be possible, he explains. These research questions may be answered in the future, Reichert concludes.

Zachery Roger Reichert, MD, PhD, discusses novel agents and pathways under exploration in prostate cancer.


Zachery Roger Reichert, MD, PhD

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Dr Reichert on Key Research Questions in Prostate Cancer

Dr Reichert on Investigating Novel Agents and Pathways in Prostate Cancer

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