Tackling Prostate Cancer with Increasing Precision
William G. Nelson
Johns Hopkins Kimmel Comprehensive Cancer Center

uring his long tenure as the head of urology at what is now the Memorial Sloan-Kettering Cancer Center, Willet F. Whitmore presciently asked whether a cure for prostate cancer was necessary for those for whom it was possible, and whether a cure was possible in those for whom it was necessary. Decades later, ongoing improvements in prostate cancer screening, detection, diagnosis, and treatment appear finally on the cusp of delivering precision medicine answers to the Whitmore query, more and more often steering the right men to the right treatment at the right time.

The introduction of serum prostate-specific antigen (PSA) testing in the 1980s revolutionized the care of prostate diseases, including prostate cancer. Still the most widely used tumor biomarker, PSA was rapidly adopted for prostate cancer screening and risk stratification, for assessing response to treatment, and for monitoring disease recurrence and progression. Now, a growing portfolio of new molecular biomarkers and imaging technologies have begun to impact the routine care of men with prostate cancer. From prostate cancer screening and early detection to treatment of life-threatening disease, these new tools increasingly stratify men into subsets that drive clinical decision-making, underpinning precision medicine approaches to prostate cancer care.

Over the past half-century, prostate cancer emerged as the most commonly diagnosed cancer among men in the US. For 2021, an estimated 248,530 new cases will be diagnosed, accompanied by 34,130 deaths. The Whitmore conundrum remains readily evident: while as many as one in eight men may be diagnosed with prostate cancer at some point in their life, the chance for men to die of the disease appears limited to only 1 in 41. Most men with prostate cancer are usually diagnosed at age 65 years or older, so any treatments must be considered in the context of other health threats.

Prostate cancer screening, using serum prostate-specific antigen (PSA) testing and digital rectal examination (DRE), clearly leads to more diagnoses of early-stage and lower-grade disease, where localized treatments are most effective at long-term cancer control. Yet, population-scale prostate cancer screening risks overdiagnosis and overtreatment of prostate cancers which men are more likely to die with rather than of. Confronting this challenge, evolving tactics focus on discerning which men with screen-detected prostate cancer can avoid aggressive interventions. Such men can be managed using active surveillance, with periodic PSA tests, DREs, magnetic resonance (MR) images, and repeat prostate biopsies as necessary. Currently, men found to have low-grade prostate cancers (Grade Group 1; Gleason score 6) are not thought to need immediate treatment. These men may well be able to avoid treatment altogether. Men with higher-grade prostate cancers (Grade Groups 2-5; Gleason score ≥7) appear to be better candidates for aggressive local therapy. Of concern, variability among pathologists assigning histologic grades, and the propensity for transrectal ultrasound (TRUS)-guided patterned biopsies to miss critical lesions, leaves significant opportunities for improvement.

Molecular Diagnostics as Disease Biomarkers

New prostate pathology tools are now rapidly being evaluated and introduced into routine practice. For histologic discrimination and grading of prostate cancer, machine learning and artificial intelligence approaches have achieved accuracy levels that will soon propel these technologies into routine clinical care. Immunohistochemistry and in situ hybridization techniques now target a growing collection of biomarkers to aid in prostate cancer diagnosis (prostate cancer cells express AMACR, MYC, NKX3.1, and ERG but not cytokeratins K5/K14, p63, or GSTP1) and risk stratification (loss of PTEN expression and high levels of MYC and Ki67 are harbingers of aggressive disease behavior). Germline sequencing for DNA double-strand break repair gene defects (BRCA1, BRCA2, ATM, and others) and DNA mismatch repair gene defects (MSH2, MLH1, and others) can help stratify men for earlier intervention and steer them toward specific treatments (PARP inhibitors for double-strand break repair deficiency; immune checkpoint inhibitors for mismatch repair deficiency). Somatic genome/epigenome alterations, inventoried using tumor sequencing methods, and gene expression assays are poised to add further tools. Already, the Prostate Health Index (PHI), 4Kscore test, MRI, Oncotype DX, Decipher test, Prolaris, ConfirmMDx, Progensa PCA3, NADiA ProsVue, and ProMark are used to change treatment decisions, decrease unnecessary biopsies, alter treatment intensity, and reclassify risk of disease progression. Prostate cancer DNA has been detected in the circulation, in prostate secretions, and in the urine, offering extraordinary opportunities to build tests capable of detecting and discriminating somatic genome/epigenome defects for use in screening and early detection (sensitive detection of common defects), in risk stratification (enumeration of high-risk versus low-risk defects), in treatment/disease monitoring (quantification of genomes/epigenomes carrying defects), and in treatment selection (inventory of defects as companion diagnostics for specific drug indications).

Advances in Prostate Cancer Imaging

Innovations in prostate imaging are impacting prostate cancer practice as well. Multi-parametric MR imaging (mpMRI), incorporating T2-weighted anatomic imaging, diffusion-weighted imaging, and contrast enhancement, is now increasingly used to direct prostate biopsies to ensure more accurate sampling of higher-grade cancer. To do so, mpMRI provides a standardized Prostate Imaging–Reporting and Data System (PI-RADS) score for individual lesions. Co-registration of mpMRI and real-time ultrasound imaging allow TRUS-guided biopsies to be directed to suspicious areas. Several nuclear medicine tools have also now been developed. Detection of metastatic prostate cancer was once only possible using 99mTc-methylene diphosphonate (MDP) bone scans and abdominopelvic computed tomography (CT) scan or MRI. Now, 18F-sodium fluoride (NaF), 11C-choline, 18F-fluciclovine (Axumin®), 68Ga-PSMA-11, and 18F-piflufolastat (Pylarify®) are all available to hunt for prostate cancer deposits throughout the body.

Precision Medicine and Prostate Cancer Treatment

Aggressive treatment approaches to localized prostate cancer principally differ in potential complications. Radical prostatectomy, performed via a robot-assisted laparoscopic approach, can be accompanied by urinary incontinence and/or sexual dysfunction. The direct irradiation of prostate cancer using implanted radioactive 125I or 103Pd sources (interstitial brachytherapy) causes irritative voiding symptoms for most men in the first few months after implant placement, and though urinary symptoms usually improve over the ensuing year, they can persist in some men. External beam radiation therapy, using CT-based treatment planning, linear accelerators with multileaf collimators delivering three-dimensional conformal treatment, and software permitting intensity-modulated radiation dose optimization, deposits radiation doses to the prostate with high accuracy. Nonetheless, side effects involving nearby tissues include rectal toxicity (early-irritation; late-rectal bleeding), urethral strictures, and erectile dysfunction.

If treatment of localized prostate cancer has resulted in a cure, the serum PSA will fall to a low or even undetectable level and remain so for the remainder of life. Rising serum PSA is a sign that prostate cancer has reappeared somewhere, though the threat of progression to symptomatic metastatic prostate cancer may not be dire: in one study, only 30% of men with a rising serum PSA after radical prostatectomy developed overt metastases within 8 years of the PSA increase. Precision medicine approaches are beginning to further shape decision-making in this setting. When coupled with new imaging approaches, the rate of serum PSA rise (doubling time) may stratify men for intervention. In a recent clinical trial for men with a rapidly rising serum PSA, 18F-piflufolastat (Pylarify®) imaging was successfully used to identify men with oligo-metastatic disease progression suitable for treatment with stereotactic ablative radiotherapy.

Several drugs are now available for systemic treatment of disseminated prostate cancer, including agents disrupting androgen action, taxane chemotherapy drugs, PARP inhibitors, immune checkpoint inhibitors, and radiopharmaceuticals. Androgen deprivation therapy (ADT), a mainstay of prostate cancer treatment for more than 80 years, is still the most commonly used intervention, usually accomplished using luteinizing hormone–releasing hormone (LHRH) analogs to suppress testosterone production and reduce circulating testosterone levels to less than 50 ng/mL. Combining ADT with taxane chemotherapy may offer improvements in disease outcomes, including overall survival, though which men should receive ADT + chemotherapy versus ADT alone has not been fully resolved, a clear unmet need for precision medicine approaches. Curiously, taxane chemotherapy looms large in prostate cancer treatment because among all of the various cytotoxic chemotherapy drugs, only those targeting intracellular microtubules (the taxanes docetaxel-Taxotere® and cabazitaxel-Jevtana®) have been shown to improve prostate cancer survival.

Most men on ADT for advanced prostate cancer inexorably progress to castration-resistant prostate cancer (CRPC). In this setting, some men with cancers still addicted to androgen signaling (and still producing PSA) respond to CYP17 inhibitors (abiraterone-Zytiga®) or to androgen receptor antagonists (enzalutamide-Xtandi®; apalutamide-Erleada®; darolutamide-Nubeqa®). A novel molecular biomarker, circulating prostate cancer cells expressing the AR mRNA splice variant V7 (AR-V7), can predict resistance to these second-line hormonal treatments and steer men instead to taxane chemotherapy. In addition, new clinical trial results paradoxically reveal that the cyclic administration of high-dose testosterone to men with CRPC can produce strikingly beneficial treatment responses, though which men are most likely to see such benefits is not clear. PARP inhibitors (olaparib-Lynparza®; rucaparib-Rubraca®; niraparib-Zejula®) exhibit activity against CRPCs with DNA double-strand break repair gene defects. For prostate cancers with DNA mismatch repair gene defects, an immune checkpoint inhibitor (pembrolizumab-Keytruda®) may promote durable treatment responses. CRPC bone metastases can be palliated with the α–particle-emitting calcium mimetic 223Ra. Finally, for CRPC exhibiting a small cell neuroendocrine phenotype, chemotherapy regimens typically used for other small cell cancers (cisplatin-Platinol® or carboplatin-Paraplatin® and etoposide-VePesid®) have been used. On the horizon are attempts to deliver radioemitters, cytotoxic drugs, and chimeric antigen receptor (CAR) T-cells selectively to prostate-specific membrane antigen (PSMA)-expressing prostate cancer cells, and strategies to combat immunosuppressive influences on the prostate tumor microenvironment (TME).

Going forward, the growing toolbox of precision medicine technologies and tactics should enable more and more men with prostate cancer to receive the right treatment at the right time, moving closer and closer to a cure, in the parlance of Willet Whitmore, when necessary. In addition, the same set of tools will allow new treatment development to proceed along more predictable pathways for molecularly defined disease subsets.

References available upon request.