Experts Discuss Emerging Targets, Diagnostics, Therapies in Advanced Prostate Cancer

Experts Discuss Emerging Targets, Diagnostics, Therapies in Advanced Prostate Cancer

Diagnosis and treatment of advanced prostate cancer continue to evolve. A better understanding of the genomics of this malignancy, as well as improved imaging techniques and developments of new therapeutics, are pushing that evolution. Several experts discussed the changing field of advanced prostate cancer management on February 8.

Dr. Padmanee Sharma speaks during General Session 2.
Padmanee Sharma, MD, PhD, of The University of Texas MD Anderson Cancer Center, spoke about the difficulties associated with using immunotherapy approaches in prostate cancer, and how some new research may help address those problems.

“We’re all trying to answer the same question over and over: Why do some patients respond and others do not?” Dr. Sharma said. As the approved indications for immune checkpoint therapy expand year after year, that question has become relevant both within a given oncologic setting and across malignancies. More specifically, outstanding questions include what cellular and molecular mechanisms are involved in antitumor effects with immunotherapy, and whether we can identify predictive, prognostic, or pharmacodynamic biomarkers to guide treatment. Ideal combination therapies with immune checkpoint inhibitors and standard-of-care therapies are also under investigation.

“Prostate cancer is poorly infiltrated by the types of cells that we expect would lead to a good immune response,” Dr. Sharma said. One of the goals of therapy would be turn the prostate tumor from a “cold” to “hot” microenvironment, with greater immune infiltrates.

Unfortunately, research has shown that treatment with the CTLA-4 inhibitor ipilimumab can have an inhibitory effect. “The immune system is tightly regulated,” Dr. Sharma said. “If you drive it one direction, it will try to compensate.”

Some immune genes show significant increases in expression after exposure to ipilimumab plus androgen deprivation therapy; these include PD-L1, CTLA-4, and VISTA. There is a sharp contrast to other malignancies; for example, Dr. Sharma said that melanoma samples show a helpful response after exposure to ipilimumab, whereas prostate samples had a not-helpful response.

Still, there are potential approaches that may overcome some of those difficulties. For example, the DynaMO trial (NCT02703623) will add ipilimumab to abiraterone and apalutamide, and compare this to cabazitaxel plus carboplatin along with the abiraterone and apalutamide regimen, in patients with metastatic castration-resistant prostate cancer (mCRPC).

There is also the possibility that targeting multiple immune checkpoints may offer benefit. A mouse study found that the combination of an anti–CTLA-4 agent with an anti–PD-1 drug offered better survival than either agent alone, and Dr. Sharma said a clinical trial using ipilimumab and nivolumab is now ongoing in CRPC.

She also noted that there are many other costimulatory and co-inhibitory pathways present. “What role these pathways play in the prostate tumor microenvironment has yet to be elucidated,” she said, adding that it is necessary to “come up with rational combination strategies to help improve the survival of these patients.”

Understanding Oligometastatic Disease

Felix Y. Feng, MD, of the University of California, San Francisco, spoke about the diagnosis and management of oligometastatic disease, defined as an intermediate state of cancer spread between localized disease and widespread metastases. Incidence of this in prostate cancer has increased, which Dr. Feng said can be attributed to the advent of PET imaging.

Even at very low PSA levels of less than 0.2 ng/mL, PET imaging offers reasonable detection of disease. It can also be used to find oligometastatic disease at initial diagnosis, Dr. Feng said. “I think it is relatively clear that the increasing use of advanced PET imaging will lead to advanced diagnosis of oligometastatic disease,” he said. The resulting question is how to treat it.

To answer that question, Dr. Feng said it is important to understand the evolution of metastatic disease. Both the primary tumor and existing metastases can seed new metastases, although the principle mode of spread is from metastases to metastases. Therefore, to cure oligometastatic disease, it may be necessary to ablate both the primary tumor and the metastases.

Attendees listen during General Session 2.
There are three basic pillars to management, he said, including prostate-directed therapy, systemic consolidative therapy, and node- and metastasis-directed therapy. There are ongoing clinical trials in each of these areas (TRoMbone; g-RAMPP, STAMPEDE, and HORRAD) that will shed some light on optimal approaches in the future. Examples of prostate-directed therapy include a phase III trial conducted by the Southwest Oncology Group, which will compare standard systemic therapy to the same plus definitive treatment (surgery or radiation) of the primary tumor in patients with metastatic disease.

With regard to node- and metastasis-directed therapy, a number of retrospective studies have been conducted, and some limited prospective data are available. The STOMP trial, published in 2017, was a phase II trial comparing active surveillance with stereotactic body radiation therapy or surgery for metastases, and it found that 75% of the patients who received metastasis-directed therapy had a PSA decline compared with only 35% of patients in the surveillance arm.

Finally, studies of intensification of systemic therapy for high-risk localized disease have shown some benefit with the approach, and Dr. Feng said that it would make sense that patients with oligometastatic would benefit most. “Ultimately, better predictors of ‘less aggressive’ versus ‘more aggressive’ oligometastatic disease are needed,” he said.

A Complicated Genomic Landscape

A better understanding of the molecular landscape of prostate cancer could obviously result in improved management of the malignancy. Kim N. Chi, MD, FRCPC, of the University of British Columbia, in Vancouver, spoke about incorporating genomics into the management of systemic therapy for CRPC.

A lot of effort has been put into genomic profiling of prostate cancer, Dr. Chi said, and this has revealed driver mutations that have clinical relevance. However, biopsies to look for some of those mutations are invasive and not always feasible in metastatic disease. Liquid biopsies, involving analysis of circulating tumor DNA (ctDNA) and cell free DNA (cfDNA), offer an alternative that permits serial sampling over a patient’s disease course. It can also be done outside of specialized centers.

Previous research has shown that ctDNA is associated with tumor burden and with treatment outcomes. Furthermore, it appears to be representative of metastatic tissue. In one study, nearly 94% of mutations detected using metastatic tissue biopsy were also detected using ctDNA analysis. In contrast, there were 109 somatic mutations detected in cfDNA, and 33% of those were not detected with tissue biopsy.

Dr. Joe M. O’Sullivan speaks during General Session 2.
Another study published this year found that a number of baseline ctDNA genomic alterations are associated with outcomes when patients were treated with abiraterone or enzalutamide. Notably, patients with a BRCA2/ATM truncating mutation, which are present in approximately 10% of patients, had more than a 5-fold increased risk of poor clinical outcomes; Dr. Chi said the hazard ratio of 5.27 (95% CI [2.79, 9.95]) “far exceeded” that of any other genomic or clinical parameter.

This and other indicators that DNA damage repair defects may be correlated with outcome have led to several trials of PARP inhibitors for CRPC, including some large phase III studies that are ongoing.

There are also indications that the PI3K pathway may be linked to abiraterone or enzalutamide outcomes, Dr. Chi said. In one study, patients with PTEN-negative disease had worse overall survival with abiraterone, whereas another showed that PTEN loss predicts the benefit from ipatasertib plus abiraterone.

“We’re going to [need] many more studies to understand the clinical utility of performing genomic analysis,” Dr. Chi said. “ctDNA can be used to identify genomic alterations in the majority of men with mCRPC and are representative of metastatic tissue biopsies. Deleterious genomic alterations … have been associated with outcomes and have the potential to inform patient management.”

Molecular Radiotherapy: An Emerging Option

Finally, Joe M. O’Sullivan, MD, of Queen’s University Belfast, in Northern Ireland, spoke about the potential of molecular therapies in bone metastases. “Targeting bone metastases really matters in mCRPC,” he said. “Up to 90% [of patients] with advanced CRPC will have metastases in their bones. In fact, bone metastases are the main cause of death in prostate cancer.”

However, he said, the phenotype of prostate cancer in the bone facilitates both imaging and therapy of these sites. The change to the normal bone environment associated with prostate cancer metastases allows the imaging with technetium-99, conjugated with methylene diphosphonate. One can deliver a radioactive payload to the metastatic site using the same basic principle.

 Molecular radiotherapy uses alpha particles, which are relatively massive and very energetic, but can only travel a short distance through tissue. “Alpha particle radiation is a very effective way of delivering high-energy radiation over a short distance,” Dr. O’Sullivan said. Radium-223 is currently being studied in this setting; it has a dual mode of action, targeting both the metastatic prostate cancer cells themselves as well as the osteoblasts and osteoclasts that can promote tumor growth.

 Some studies have shown benefit with radium-223. The ALSYMPCA trial showed an overall survival benefit of 3.6 months, which was statistically significant, with radium-223 plus best standard care, compared with placebo and best standard care. There was also a substantial delay in the time to first skeletal event (15.6 months vs. 9.8 months; p < 0.001). Dr. O’Sullivan noted, though, that other trials such as the ERA-223 study have had unexpected findings, including higher rates of treatment-emergent fractures and other skeletal events. He hypothesized that the timing of the therapies is important; in that trial, abiraterone and radium-223 were started at the same time, which may have led to some of the problems.

“We are in a new era for bone-targeted therapy with molecular radiotherapy,” Dr. O’Sullivan said. “But questions still remain.”

–Dave Levitan