The Challenge of Precision Medicine in mCRPC

Raoul S. Concepcion, MD, FACS

Over the past decade, we have used the terms personalized medicine and precision medicine interchangeably. For the most part, patient care has always been personalized. Yes, some want to make it more standardized. Still, to adequately manage and treat our patients, we have to consider many comorbidities when providing a treatment benefit that minimizes the impact on quality of life. For example, what should be the oral agent of choice as first or second line of therapy in the management of metastatic castration-resistant prostate cancer (mCRPC)? Or, if a patient has localized prostate cancer, will surgery or radiation therapy provide the best chance of cure? It all depends.

In the first scenario, we would base our choice of oral therapies on the patient’s medical history, which, if significant, might give rise to a deleterious adverse event associated with the drug. In the latter, it is doubtful that we would think that radical prostatectomy would be the best choice for a patient with significant local disease who has had multiple abdominal/pelvic surgeries. We would all agree that fully understanding our patients’ medical histories helps to guide our final recommendations, regardless of whether we are writing a prescription or recommending surgery. This is personalized care.

We have now entered the era of precision medicine. In 1971, President Nixon declared a “war on cancer” by signing the National Cancer Act. Those of us who are old enough to remember Operation Desert Shield and Operation Desert Storm in 1990 and 1991 witnessed for the first time, as a result of live media coverage of frontline fighting, the use of radio- or laser-guided smart bombs that minimized collateral damage and required less explosive to damage a target. Essentially, that is what we are trying to achieve as we explore the biology of cancer. What are the molecular drivers that result in recurrence and resistance to therapy? More important, after we have identified the mechanisms, is it possible in some cases to target these pathways and minimize toxicity to healthy cells? Success in this regard amounts to a lessening of collateral damage.

This is the promise of precision medicine, which is mandated when we have multiple options for the same patient type. In localized prostate cancer, we now have genetic tissue assays that can potentially assist us in our shared decision making. This is particularly true if a patient has a lower risk for progression and is a candidate for active surveillance, thus potentially limiting qualityof- life issues that may result from active treatment. For our patients with muscle invasive bladder cancer, in which neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care, use of molecular subtyping may help identify which patients are unlikely to respond to NAC, making it possible for them to move directly to surgery and avoid the toxicity of methotrexate, vinblastine, doxorubicin, cisplatin, or gemcitabine and cisplatin. In the future, with this molecular subtype information, we might be able to identify patients in that 30% category who are complete responders to NAC and could avoid life-altering surgery entirely.

Case in point: Among patients with mCRPC who have been heavily pretreated with multiple lines of current therapy, immunotherapy seems to benefit those who test positive for microsatellite instability (MSI) or have biallelic loss of CDK12 with inactivation. We are also well aware of androgen receptor (AR) splice variant mutations that seem to directly correlate with treatment pressure selection, limiting the subsequent use of AR modulating agents. Testing for this in select patients will be essential, as we have more and more approved agents. Finally, because we have now established that lethal prostate cancer has a definite hereditary pattern, it will be imperative to incorporate genetic testing panels for potential treatment selection as well as to provide adequate family counseling.

Nothing has been stated in this missive that we have not heard before. For the most part, all of us entered urology, especially urologic oncology, for the challenge and satisfaction of extirpative surgery and reconstruction. However, to remain leaders in the management of our oncologic patients, we need to have total knowledge of the disease and not limit ourselves to the adoption of and adaptation to newer surgical techniques. It may take a restructuring of our current practice models, but we need to embrace, understand, and incorporate all these new technologies, both surgical and nonsurgical, to be at the forefront of precision medicine for our patients.

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For our patients with mCRPC, the concept of precision medicine and testing becomes even more critical. After the early tsunami of novel agents that received FDA approval in the first half of this decade, we have seen movement of these therapies to more proximal stages but nothing new mechanistically. As we know, this will undoubtedly change by year’s end. Regardless of whether these new agents are PARP inhibitors, theranostic agents, or others, they will only add to the complexity of how to best layer or sequence therapies when treating patients with mCRPC. Furthermore, we are now in the infancy of predictive and prognostic molecular testing that will provide key information regarding resistance pathways but more than likely will be mandated for use with particular agents.