Metastatic Prostate Cancer
Biomarker-Driven Targeted Treatments in Metastatic Castration-Resistant Prostate Cancer
Data presented at the ESMO Congress 2021 highlight the potential of biomarker-driven therapies in the treatment of advanced prostate cancer. These strategies range from novel poly (ADP-ribose) polymerase (PARP) inhibitor combinations to prostate-specific membrane antigen (PSMA)–targeted radioligand therapy.
Following the presentations, featured expert Robert Dreicer, MD, MS, MACP, FASCO, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Dreicer’s perspectives on the emerging data are presented here.
Section Head, Medical Oncology
“Another biomarker that is really gaining attention is PSMA, which is a theranostic molecular biomarker, meaning that it is useful in both imaging and therapeutics.”
It is still in the early days for biomarker-driven therapeutics in prostate cancer, but the data presented at the ESMO Congress 2021 continue to add to the knowledge base in metastatic castration-resistant prostate cancer (mCRPC). We have 2 US Food and Drug Administration (FDA)–approved PARP inhibitors in the United States: olaparib and rucaparib.
What we saw at the meeting was quite a bit of early work exploring variations of a theme using other PARP inhibitors such as niraparib alone or in combination with agents such as pembrolizumab. The FDA-approved PARP inhibitors have their most significant activity in patients with BRCA2 and BRCA1 mutations, and, perhaps to a lesser extent, in those with ATM mutations. Further, although a recent press release suggests that the olaparib-plus-abiraterone combination improves radiographic progression-free survival in men with mCRPC in the phase 3 PROpel study, we have limited data on the use of other PARP combinations. So, from a biomarker-driven therapy perspective, there is clearly more work to be done here.
PTEN loss is a predictive biomarker for AKT inhibition, another important molecular target in mCRPC. The phase 3 IPATential150 trial exploring combination therapy with the AKT inhibitor ipatasertib plus abiraterone was not a positive study, as it was originally intended; however, there was apparent activity in patients who had evidence of PTEN loss. Some of the safety data were reported by Sternberg and colleagues at the ESMO Congress 2021 (abstract 585P). While this combination does seem to have activity, there is a fair amount of toxicity associated with this regimen. So, a lot more research is needed in this space. Further, as noted above, the recent preliminary data from the PROpel trial are provocative, and we await a presentation of these data at an upcoming scientific congress, along with overall survival data.
Another biomarker that is really gaining attention is PSMA, which is a theranostic molecular biomarker, meaning that it is useful in both imaging and therapeutics. PSMA positron emission tomography/computed tomography has been regulatorily approved by the FDA in the United States and will probably replace conventional imaging because of its sensitivity and specificity. There are several PSMA-targeted radioligand therapeutic molecules in this space, but lutetium-177–PSMA-617 is receiving the most attention, as it is the furthest along in development. It has been tested in the phase 3 VISION study, which demonstrated a survival benefit. Trials in progress include the randomized phase 3 PSMAddition study (abstract 647TiP), which is investigating targeted radioligand therapy in mCRPC, and the randomized phase 3 PSMAfore study (abstract 648TiP), which is looking at taxane-naive patients with progressive mCRPC and confirmed PSMA expression. Additionally, interim data from the phase 1b PRINCE trial were presented at the ESMO Congress 2021, wherein lutetium and pembrolizumab were combined (abstract 5770).
It should be noted that PSMA is expressed at some level in approximately 85% of patients; thus, it is a potentially broadly viable target. In the near term, there are a number of important questions that need resolution. For instance, will demonstrating PSMA positivity by positron emission tomography/computed tomography be required for lutetium use, based on an FDA-approved label? Additionally, we would like to know whether we can upregulate PSMA expression in the tumor and whether that can be used to improve outcomes. Many people who work in this space recognize that we are very early in this exploration, and, even though our Australian and European colleagues have been using this agent in a variety of settings for several years now, much more work needs to be done. That said, this area holds great promise, and I will be following developments here closely.
ClinicalTrials.gov. Study on olaparib plus abiraterone as first-line therapy in men with metastatic castration-resistant prostate cancer. Accessed October 6, 2021. https://clinicaltrials.gov/ct2/show/NCT03732820
Lynparza in combination with abiraterone significantly delayed disease progression in all-comers in PROpel phase III trial in 1st-line metastatic castration-resistant prostate cancer. News release. AstraZeneca. September 24, 2021. Accessed October 6, 2021. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/lynparza-propel-trial-meets-primary-endpoint.html
Morris MJ, de Bono JS, Chi K, et al; VISION Trial Investigators. Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol. 2021;39(suppl 18):LBA4. doi:10.1200/JCO.2021.39.15_suppl.LBA4
Morris MJ, Sartor O, Chi KN, et al. PSMAfore: a phase III study to compare 177Lu-PSMA-617 treatment with a change in androgen receptor pathway inhibitor in taxane-naïve patients with mCRPC [abstract 648TiP]. Abstract presented at: ESMO Congress 2021; September 16-21, 2021.
Sandhu SK, Joshua AM, Emmett L, et al. PRINCE: interim analysis of the phase Ib study of <sup>177</sup>Lu-PSMA-617 in combination with pembrolizumab for metastatic castration resistant prostate cancer (mCRPC) [abstract 5770]. Abstract presented at: ESMO Congress 2021; September 16-21, 2021.
Sartor O, de Bono J, Chi KN, et al; VISION Investigators. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322
Sternberg CN, Bracarda S, de Bono JS, et al. Safety analysis of the phase III IPATential150 trial of ipatasertib (ipat) plus abiraterone (abi) in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract 585P]. Abstract presented at: ESMO Congress 2021; September 16-21, 2021.
Tagawa ST, Sartor O, Saad F, et al. PSMAddition: a phase III trial to compare treatment with 177Lu-PSMA-617 plus standard of care (SOC) versus SOC alone in patients with metastatic hormone-sensitive prostate cancer [abstract 647TiP]. Abstract presented at: ESMO Congress 2021; September 16-21, 2021.
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