(UroToday.com) In this panel discussion, the presenters answered questions from the audience on the prior session, which are summarized here.
Question: In ovarian cancer, perhaps one of the most effective means to predict response to PARPi is prior response to platinum, irrespective of HRD status. Thoughts for prostate cancer?
Dr. Nelson answered that this question comes back to the challenging complexity of truly defining homologous recombination deficiency beyond mutations in HR genes. He summarized the alternative biomarkers of HR deficiency such as genomic scars and mutational signatures that may be more effective in identifying patients that respond to platinum as well as PARP inhibition. Finally, he noted that there are trials looking at PARP inhibitor maintenance after platinum chemotherapy in advanced prostate cancer (NCT04592237, for example).
Question: What will be the most accurate biomarkers for PARP sensitivity?
This is an area of ongoing investigation. Dr. Nelson answered this question citing the FDA requirement of post-marketing studies for Olaparib. These will hopefully include study of the two genes, RAD51C and FANCL that were not present in any patient enrolled on PROfound. Multiple other PARP inhibitors are currently undergoing evaluation including niraparib and talozoparib, which may help refine the specific gene mutations and other genomic contexts/assay readouts that are related to robust response.
Question: What are possible composite biomarkers for the efficacy of PTEN targeting agents, especially since prior trials targeting this pathway have not been positive.
Dr. Gleave answered this question affirming that many agents trialed previously have not shown efficacy or have dose limiting toxicities. The reasons for this are complex and likely depend on the disease context and underlying biology, and whether there are compensatory pathways that promote tumor growth while under treatment with a specific inhibitor. Indeed, biological redundancies and complex dependencies limit single agent activity, which is why many studies now including AKT inhibitors use co-targeting strategies. Composite biomarkers may be necessary to most accurately stratify patients for therapy. For now, IHC for PTEN loss works reasonably well because PTEN loss is usually deep/homozygous resulting in significant loss of expression. However, adding in NGS assays will help the performance of a biomarker in that it can detect loss of function mutations and can detect other alterations in the PI3K pathway.
Question: How do you envision sequencing all the available radiopharmaceutical therapies? Will it be a situation where you can use only one and be done, or might you be able to use more?
Dr. Sathekge discussed that there may be additional benefit from therapy with an alpha emitter such as actinium beyond the benefit of lutetium, especially because you can avoid some of the toxicity of lutetium therapeutics with actinium such as salivary gland toxicity. However, much work needs to still be done to best understand how to sequence these therapies, and if it is even possible.
Question: Despite 67% of patients responding to lutetium, many patients progress quickly. Is this a durability issue with PSMA-targeted therapeutics?
Dr. Hoffman answered this question by emphasizing the overall hazard ratio for progression (figure shown below from same day publication.1 As shown in our paper, somewhere around 20% of patients do have longer term responses, but more work is required to explore ways to prolong the durability of treatment.
Question: What is the future of personalized vaccines in prostate cancer?
Dr. Autio answered that personalized vaccines catered to a patient’s specific MHC expression certainly may be developed in the future, but there are many challenges that need to be addressed. Vaccine design predictions are imperfect, and cost will be an issue. However, this may be one way to try an alternative immune therapeutic strategy that is not dependent on a high tumor mutational burden.
Peter Nelson, MD, Fred Hutch, University of Washington School of Medicine
Martin Gleave, MD, FRCSC, FACS, University of British Columbia
Karen A. Autio, MD, MSc, Memorial Sloan Kettering Cancer Center
Mike Sathekge, MBChB, MMed (Nucl Med), PhD, University of Pretoria and Steve Biko Academic Hospital
Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021
1. Hofman M, Emmett L, Sandhu S, et al., [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. The Lancet 2021
ASCO GU 2021: PARP Inhibitors – Is It A Sea Change or Just Another Incremental Change?
ASCO GU 2021: Back to Basics in Personalization: Returning to PTEN
ASCO GU 2021: Beyond the Basics: Harnessing the Immune System to Fight Prostate Cancer
ASCO GU 2021: Lighting the Way: Lutetium in the Treatment Paradigm