THE CHECKPOINT INHIBITORS – In Search of a Role in the Treatment of Prostate cancer: The Current Status
The August issue of PCa Commentary discusses the current status of using checkpoint inhibitors for treating prostate cancer, including results from the Keynote-028 and Keynote-199 looking at the efficacy of pembrolizumab in heavily penetrated patients. He further discusses results related to the BRCA family of gene mutations, links between the gut microbiome and checkpoint inhibitors, as well as detailing two current clinical trials (Keynote 365 and Checkmate 9KD) examining combination therapy in mCRPC patients.
ANTI-PSMA 177-LUTETIUM RADIOLIGAND THERAPY:
An Update on Outcomes; the Vision Trial; and Future Directions
The February / March issue of PCa Commentary discusses using anti-PSMA 177-lutetium radioligand therapy for treating advanced metastatic prostate cancer. Dr. Weber examines the background of this therapy, early trials, and details the results of the VISION Trial. He further examines future implications and possibilities for this therapy in treating advanced metastatic prostate cancer.
ANTI-TUMOR IMMUNE RESPONSE POTENTIATED by RADIOTHERAPY:
A concept arising from pre-clinical studies is now clinically supported by the results of the ORIOLE trial.
January’s issue of PCa Commentary discusses the implications of the ORIOLE Trial, which examined the effects of patients of primary radiotherapy or surgery on patients with mHSPC, as well as looking at pre-treatment imaging and genomic data to look at mechanisms explaining progression-free survival in both groups. The study found that the use of SART improved progression-free survival and found no additional bone lesions in the group.
PARP INHIBITION THERAPY — Clinical Importance of Genetic Variants of BRCA 1/2 and ATM in Men with Metastatic Castration-Resistant Prostate Cancer.
December’s issue of PCa Commentary discusses PARP inhibitor therapy as a potential new entry into the regimens of standard-of-care treatment for metastatic castration-resistant prostate cancer patients with BRCA 1/2 and ATM mutations. This Commentary highlights findings from the late-breaking PROfound trial, which evaluated olaparib for the treatment of heavily pretreated men with DNA damage repair (DDR) alterations and reported impressive results.
Role of Androgen Suppression Added to Salvage Radiotherapy Following Prostatectomy for High-Risk Prostate Cancer: In Selected Cases, No Benefit and Associated Harm
The findings from this randomized Phase III trial supported the current standard of care for this situation. It compared two treatments initiated after a PSA rise to levels between 0.2 – 4.0 ng/mL after a prostatectomy and lymphadenectomy. The study involved 761 men with localized cancer having a high risk for recurrence, i.e., extracapsular extension or seminal vesicle involvement, or nodular disease with positive surgical margins. Salvage radiation to the prostate region was given to all.
OLIGOMETASTATIC PROSTATE CANCER: Is It an Intermediate Stage of Cancer, and If So, How Should It Be treated?
It has been suggested that a few (usually 3-5, i.e., ‘oligometastatic’) lesions at the time of biochemical failure after primary treatment might represent an indolent disease state with limited potential for additional spread. This hypothesis was first made in 1995 by Hellman and Weichselbaum (J Clin Oncol). Those authors’ thoughts were paraphrased by Tran and Antonarakis (J Oncol Pract. 2016) in “Altering the Natural History of Oligometastatic Prostate Cancer with Local Therapies: Reality Versus Illusion.”
Active Surveillance: Update and New Developments
This issue reviews the current state of active surveillance with an article from Laurence Klotz, MD, entitled “Active Surveillance for Prostate Cancer: How to Do It Right.” This Commentary covers the role of multiparametric MRI and genomic testing panels in carefully selecting and following prostate cancer patients who choose active surveillance in order to safely delay primary treatment and achieve excellent outcomes.
Radium-223 (‘Xofigo’): A Radioisotope Treatment for Bone Metastases – Where Does It Fit in the Management of Prostate Cancer?
This issue reviews the clinical significance of bone metastases in castrate-resistant prostate cancer (CRPC) patients, the mechanism of action of radium-223, and the isotope’s utility in managing these patients. This Commentary also features take-away points from a lecture titled “Real World Treatment Experience with Radium-223” by Daniel George, MD, on the role of radium-223 in the schema of metastatic CRPC treatment.
The Natural History of Prostate Cancer and the Prognostic Utility of PSA Doubling Time.
This issue reviews a report Catherine H. Marshall, MD, MPH, presented at the 2019 ASCO Annual Meeting, entitled “Outcomes of Men with Recurrent M0 Prostate Cancer Who Defer Androgen Deprivation Therapy Until Metastasis – Medical Oncologist Perspective.” The discussion will analyze outcome data from three retrospective related observation trials included in Dr. Marshall’s report, and how PSA doubling time can guide appropriate timing of hormone suppression initiation so as to balance the dual goals of delaying metastases and avoiding the toxicity of therapy.
Managing PSA Recurrence Following Primary Radiation Therapy: Evolving Regimens for Focal Treatment.
Biochemical recurrence following primary irradiation is relatively common. “A recent series of 2694 patients treated with doses above 78 Gy revealed 10-year biochemical recurrence risks of approximately 10%, 23%, and 44% in low-, intermediate-, and high-risk patients, respectively. […] After primary whole-gland radiotherapy several series showed that nearly all recurrences (89-100%) regrow at the site of the primary largest and/or highest-grade index lesion,” as quoted in “Focal Salvage Treatment of Radiorecurrent Prostate Cancer”, Marieke et al., Cancers (Basel). 2018 Dec. [An excellent review] This biology offers carefully selected patients the opportunity of treatment focused on the control of the local disease recurrence.
RADIOLIGAND THERAPY – The “VISION” Protocol: A treatment opportunity for men with late-stage metastatic castration-resistant prostate cancer.
Radioligand therapy (RLT), or in other words, PSMA directed endoradiation with Lutetium-177, has been developed to the extent that it is a realistic option for men with late-stage, heavily pretreated, metastatic castration-resistant prostate cancer. This therapy has been extensively studied in many trials with the general consensus that the treatment is safe with minimal adverse effects and consistently has led to a >50% decline in PSA in a range of ~40 to 60% of the men. This Commentary will highlight examples of these studies.
GENOMIC SEQUENCING FOR PROSTATE CANCER – Which Men Gain a Clinical Benefit from Genomic Testing?
The commonly cited goal of ‘personalized medicine’ in regards to treatment selection based on genomic testing is in the early ‘work in progress’ stage. Breathtaking advances in next generation sequencing (NGS) are very promising, but currently only limited options exist for therapeutic guidance. Dr. Oliver Sartor acknowledges this in the recent NEJM review, Metastatic Prostate Cancer, Feb 2018: “The use of advanced genomic analysis is now feasible to a greater extent than ever before. Whether its use improves treatment decisions is not yet clear.”
Resistance to Therapeutic Agents Targeting the Androgen Receptor and Insights into Sequencing Treatments for Optimal Outcomes
Ever since the first orchiectomy for metastatic prostate cancer in 1941, researchers and clinicians have been determinedly trying to restrain the androgen receptor (AR) by manipulating its hormone environment. But like Houdini, after initial suppression this wily adversary wriggles a bit and then escapes — transitioning prostate cancer into a castration-resistant state. Alterations in the AR eventually frustrate the beneficial gains from LHRH inhibitors and anti-androgens like Zytiga, Xtandi, Erleada, etc. This escape is accomplished by a variety of different mechanisms, presenting the challenge of anticipating and circumventing the persistence of AR signaling.
ENZALUTAMIDE (‘XTANDI’): AN UPDATE: The Many Faces of Enzalutamide
Many important developments have taken place since Enzalutamide (ENZ) was reviewed in the March/April 2014 issue. This Commentary will discuss these developments and the current indications for ENZ and new studies of ENZ as monotherapy. A subsequent Commentary will address sequencing, resistance, and possible potentiation of immunotherapy.
Ga68-PSMA-11 PET/CT Scanning at Initial Diagnosis for High-Risk Prostate Cancer: What is missed by conventional staging and does it matter?
For this Commentary, eleven research papers reporting the results for the Ga68-PSMA PET/CT applied to high-risk prostate cancer were reviewed. For interest, here is the list of research locations: Australia (3, where the scan is readily available), India, Turkey, Germany (2), Jordan, and the USA (3, UCSF, UCLA, and Johns Hopkins).
THE AXUMIN PET/CT SCAN: ITS CLINICAL UTILITY — AN UPDATE
It has been one year since the Commentary featured the Axumin PET/CT in the November 2017 issue. A great deal of new research about this scan performance has been published since then. The material in this issue is based on this research. Overall, these studies focus on the Axumin scan, which provides clinically relevant information at PSA levels that lead to significant changes in treatment plans for a majority of men.
IMMUNOTHERAPY FOR PROSTATE CANCER:
Immune Checkpoint Inhibitors — The Search for Clues for Which Men Will Benefit and How Best to Treat Them.
Harnessing our immune system to treat cancer has been an elusive goal for decades. Research in immunotherapy is intense with active study of the newest advances, i.e. checkpoint inhibitors and CAR T-cell technology. Checkpoint inhibitors have yielded encouraging results in selected patients (10% – 40% responding) with melanoma, bladder and kidney, non-small cell lung cancer, and cancer of the head and neck. However, the results of prostate cancer immunotherapy have been disappointing in unselected patients. Why is this?
DECIPHER AND A HYBRID CLINICAL – GENOMIC CLASSIFIER:
Improving the Prognostic Accuracy of NCCN Risk Categories
The article will discuss how Decipher is constructed, its benefits as a supplement to the standard risk assessments tools, and offer examples of its use in clinical practice. Additionally, the Commentary will highlight the work of Dr. Dan Spratt and colleagues that integrates the NCCN system with Decipher to achieve further prognostic accuracy (“Spratt, et al., Journal of Clinical Oncology, Feb. 2018”).
ESTROGEN — OUR SISTER HORMONE:
Addressing the Dark Side of Androgen Deprivation Therapy (ADT)
Many of the important adverse effects associated with androgen suppression with Lupron, Firmagon, or orchiectomy result from estrogen deficiency. Estimates vary, but 50%, 75%, or as much as 80% of a man’s serum estrogen arises from enzymatic conversion of serum testosterone. And when ADT drops serum testosterone into the low range of 20 – 30 ng/dL, a profound estrogen deficiency results.
NEUROENDOCRINE PROSTATE CANCER: An Adverse Development in Advanced Disease — Which Largely Has Flown Under the Radar.
Neuroendocrine prostate cancer (NEPC) is a form of the disease which, as best currently understood, arises from standard adenocarcinoma in a process termed “transdifferentiation.” This transformation develops in advanced stages of prostate cancer—usually in metastatic CRPC, and is thought to result as an adaptation to the selective pressure of androgen deprivation. It’s usually seen after prior therapy with, for example, abiraterone and/or enzalutamide and is one source of resistance to these agents.
ACTIVE SURVEILLANCE: EFFORTS TO IMPROVE ITS PERFORMANCE
The goal of active surveillance (AS) is to delay treatment, avoiding its associated adverse effects for as long as appropriate, while ensuring that selective delayed intervention will still result in a good outcome. This management strategy has been under development for more than 20 years. It has been increasingly accepted as an appropriate option for men with low-risk disease, but further refinement is required in patient selection and monitoring strategy.
RADIOLIGAND THERAPY (RLT) with 177-LUTETIUM
PSMA is a transmembrane protein of 750 amino acids expressed on the surface of ~90-95% of prostate cancer cells, increasingly expressed as aggressiveness increases. The expression of PSMA is negatively related to androgen receptor abundance so that ADT promotes increased PSMA expression. Its normal function is to ferry nutrients such as folate and glutamate into the cell to support growth and metabolism. Short sections of this convoluted protein molecule can be targeted and linked by small molecules (e.g., “617”) or antibodies (e.g., “J591”). These molecules can be fused to radiation emitting nuclides such as Lutetium-177, Actinium-225, or several others under investigation.
New Guidance on the Management of PSA Rise in the Setting of Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC)
At the 2018 Genitourinary Session of the American Association of Clinical Oncology, two presentations reported similar findings which offer management guidance for men whose PSAs are rising despite androgen suppression but have no objective evidence of metastatic spread. For men with metastases, Zytiga and Xtandi are commonly prescribed, but to date there have been no approved treatments for therapy at the nonmetastatic CRPC stage.
AR-V7: The Clinical Utility of Knowing Your Status … And When the Information Is Most Useful.
A test for the splice-variant AR-V7, Oncotype Dx AR-V7 Nucleus Detect (Genomic Health, Inc.), has become commercially available. This Commentary will focus on the clinical significance of test results — their predictive and prognostic value.
METASTASIS DIRECTED THERAPY:
What Can Be Learned From The First Reported Prospective, Randomized, Multicenter Phase II Clinical Trial?
In December 2017, the JCO published the trial results of Ost and colleagues: “Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence.”1 Up to this time, there have been numerous retrospective and observational studies of varying design which, taken together, strongly suggest that progression-free survival can be prolonged by the focal treatment of three or fewer lesions at the time of PSA recurrence after primary therapy. This regimen is now termed “metastasis-directed therapy” (MDT) and was discussed in detail in an earlier Commentary.
KNOW YOUR BRCA STATUS:
The Clinical Importance of Mutations in Genes that Repair Injury to DNA
The message is clear. At diagnosis, 6% of men carry mutations in the BRCA1 or BRCA2 gene. At the stage of metastatic castration-resistant prostate cancer, nearly 12% of men exhibit these germline (inherited) mutations. Finally, as the course of the disease progresses through various therapies, the number of BRCA and BRCA-like mutations further increases and can be found in up to 23% of men.