ASCO 2021: The New Avengers in the Treatment of Prostate Cancer

( In the plenary program of the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Johann de Bono discussed emerging treatment options in advanced prostate cancer within a session entitled “Beyond the Androgen Receptor: New Avengers in the Treatment of Castrate-Resistant Metastatic Cancer.”

To begin, Dr. De Bono emphasized that treatment options in advanced prostate cancer are rapidly changing and increasingly complex. The use of the same or related treatment approaches across various prostate cancer disease states adds complexity to the process of treatment selection and sequencing.

He emphasized that prostate cancer is many different diseases, even within the same patient. Thus, he emphasized that the key to optimizing treatment moving forward will be the identification and utilization of better biomarkers. Beyond simply identifying these markers, there is considerable work to be done regarding how to interpret the complexity of biomarker data and make this actionable for our patients. He suggested that relevant biomarkers may include imaging approaches (including PSMA PET and whole-body MRI), tumor tissue molecular characterization (through next-generation sequencing and immunohistochemistry), and blood-based biomarkers. The last of these, blood-based biomarkers, is potentially the most complex given that much of the available DNA is “normal” non-tumor-related DNA, with a low tumor-related (ctDNA) fraction.

However, these biomarkers will, in Dr. De Bono’s view, improve treatment and associated outcomes including survival and quality of life. Further, we will identify germline alterations resulting in cascade family testing and targeted prevention. However, there is a currently large and unaddressed question of how we should test including approaches such as targeted next-generation sequencing panels or immunohistochemistry for important proteins such as MMR proteins, PTEN, and ATM. He suggested that we will need to use multiple tests with orthogonal use.

In terms of prostate cancer heterogeneity, Dr. De Bono highlighted that PTEN is lost in 40-50% of advanced prostate cancer and is associated with a worse prognosis. However, these patients may benefit from combined blockage of both the androgen receptor pathway and the AKT pathway. In addition to PTEN, at least 10% of patients with advanced prostate cancer have homologous recombination repair defects affecting BRCA1, BRCA2, PALB2, RAD51, and others. These again are associated with a worse prognosis but may be targeted with PARP inhibitors or carboplatin. Similarly, patients with ATM alterations represent 10-15% of advanced prostate cancer patients and may respond to PARP inhibitors or carboplatin. While less common (3-5%), mismatch repair defects may confer sensitivity to immune checkpoint inhibition using anti-PD-1 and anti-PD-L1 agents. Finally, CDK12 is bi-allelically lost in 3-5% of patients and is associated with a poor prognosis. Patients with CDK12 loss may be sensitive to immune checkpoint inhibitors though these data are very early. Dr. De Bono emphasized that in most cases, bi-allelic loss is needed to sensitize to relevant targeted treatments.

In the context of all of these treatment approaches, he emphasized that the STAMPEDE trial has supported the use of local radiotherapy. Thus, we should consider the wide variety of treatment approaches. Further, he emphasized the growing role of radionuclides.

Dr. De Bono then focused on the role of PARP inhibition in advanced prostate cancer. He emphasized data from cohort A of the PROfound trial in which patients had a loss of BRCA1, BRCA2, or ATM. These patients derived benefit from treatment with olaparib, and the greatest benefit among those with BRCA1 and BRCA2. However, there may be benefits among others with homologous recombination repair defects. He emphasized that, when considering overall survival, the PROfound trial allowed for cross-over. Within cohort A, Dr. De Bono highlighted that subgroups of patients defined based on demographic characteristics showed a relatively consistent benefit of olaparib. Dr. De Bono then presented data from cohort B, comprising a variety of other homologous recombination repair defects which showed no benefit to the use of olaparib. He then provided a gene-level analysis suggesting that patients with BRCA1 and BRCA2 alterations are those that derive the benefit from PARP inhibition.

Olaparib had increased rates of anemia, nausea, and fatigue compared to the control approach. However, Dr. De Bono suggested that olaparib was better tolerated than chemotherapy.

Dr. De Bono took some time to focus on ATM alterations. While only 29 patients with ATM alterations received olaparib, there was evidence of some benefit. However, it appears that bi-allelic loss is required to derive benefit. Further, he highlighted that ATM loss can be spatially heterogeneous with some cells exhibiting loss and others retaining function within the same biopsy specimen. Further, for each patient, the mutational landscape can change over time from HSPC to mCRPC. Interestingly, in advanced disease, ATM loss is not prognostic.

Moving forward, he considered the rapidly evolving landscape. Most imminently, the VISION trial supports the use of PSMA-targeted lutetium radionuclide therapy. Ongoing work is assessing many other PSMA-targeted ligands including alpha-particle emitters, and bi-specific and tri-specific antibody constructs. Further, pharmacotherapy development is rapidly moving forward with AKT inhibition, drugs targeting androgen receptor splice variants, other synthetic lethal strategies (such as ATR inhibition), and targeting of myeloid-derived suppressor cells.

In conclusion, he emphasized that there are a rapidly increasing number of treatment options. As a result, men with advanced prostate cancer are living longer than before. Further, molecular stratification is an increasingly important part of care, though how to interpret and act on these data is an evolving area.

Presented by: Johann de Bono, MB ChB FRCP MSc Ph.D. FMedSci. Professor Johann de Bono is Regius Professor of Cancer Research and a Professor in Experimental Cancer Medicine at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021
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