Dr. Garje discusses mutations linked to more aggressive prostate cancer

In a recent interview with our sister site Targeted Oncology, Rohan Garje, MD, chief of genitourinary oncology at the Miami Cancer Institute, discussed his research study that showed an association between harboring TP53, RB1, and PTEN mutations and worse overall survival outcomes in patients with metastatic prostate cancer.¹

Can you provide an overview of this multicenter study?

Rohan Garje, MD

Garje: This was a collaboration with Guardian Research Network, which has data from multiple community-based oncology centers, and this study is focusing on prostate cancer where we explored their database to see if alterations and specific mutations have an impact on survival in patients with metastatic prostate cancer. It is a database which involves several organizations where we identified patients with metastatic prostate cancer and genetic testing.

One of the biggest limitations currently with prostate cancer management is we do not have risk stratification based on the patient's genomic alterations. In this sense, for anyone with metastatic prostate cancer, our way of identifying high-risk or low-risk populations is based on whether they have high-volume disease or low-volume disease, either they have de novo metastatic disease or metachronous presentation. These are all good classifiers, and they are easy to obtain parameters, but they do not consider the patient's inherent genomics, the molecular alterations that are driving the cancer.

We have a lot of information from the multiple studies that have been done [showing] that all [patients with] prostate cancer do not behave the same, and the genomic markers that drive the cancer critical. We know about HRR mutations, specifically BRCA1 and BRCA2, which are not only prognostic, but also predictive of specific treatments, that patients will benefit with [poly-ADP ribose polymerase (PARP)] inhibitors in that situation. In this particular project, what we looked at was other alterations in the more common alterations which we see in prostate cancer, which is the TP53 mutation, RB1, or PTEN, to see if any 1 of these or a combination of these mutations, if they are present, how do they impact patients compared [with] patients who do not have these mutations?

How was this study designed to assess the influence of these mutations on overall survival?

It is a multi-institutional, retrospective project where we [obtained] data through chart reviews, so it represents the real-world samples. We identified patients who had mutations, who had tumor genomic testing done, and excluded patients who did not have the tests or did not have the results. We also wanted to follow patients long-term, so we selected patients who had a minimum follow-up of a particular period where they received some sort of treatment to have some assessments for survival.

In the study, we looked for all [patients with] advanced prostate cancer who received treatment and divided them into 2 groups. The first group [was] named as biomarker-positive, and the second group was biomarker negative. The biomarker positive included 1 of the 3 gene alterations, either 1 of them, 2 of them, or 3 of them together. It could be PTEN, RB1, or TP53. The biomarker-negative group had none of those mutations. We followed these patients' treatment goals to see what their overall survival was.

Please explain the findings from this study.

Out of 350 patients that were evaluated in this cohort, the biomarker-positive [group], the patients who had 1 of these genes altered, had inferior survival, and it was significant in a multigroup analysis. What we saw was the median survival was around 35.8 months for patients who had biomarker-positive disease. For those who did not have any of these mutations, the median was almost 67 months, so there was a big difference. In the group, we also saw that patients who had these biomarker changes had more bone or liver metastatic disease at presentation. It is an important finding, which makes us question, are we treating all patients in a similar way, or should we do more precision oncology-based medicine where we pick patients at a high-risk of developing disease progression and intensify treatment? Then for folks doing well, can we deintensify treatment?

In the last few years, there has been a lot of enthusiasm to intensify therapy in upfront metastatic castration-sensitive prostate cancer, either it being combination of [androgen deprivation therapy (ADT)] along with androgen receptor pathway inhibitors, or the triplet therapy, which is the combination of ADT, androgen receptor pathway inhibitors, and docetaxel. But obviously, the concern is, are we overtreating some [patients and] are we exposing them to toxicities? The whole idea of this study is to envision scenarios where, in addition to the clinical parameters which we currently utilize to differentiate people with high-risk or low-risk disease, can we incorporate their genomic changes? Hopefully, this can better segregate patients. As we have shown in this study and also seen in some other smaller retrospective studies, these mutations are poor predictors of outcomes. Evaluating newer targeted therapeutic agents that can impact the effects of these genes and improve their survival is critical. There are some studies which are currently evaluating if [other] agents that affect these pathways of gene mutations can improve survival, so we are excited to see that. There are some studies that are being run in [patients] with these mutations to see if this can improve their outcomes.

What were the most significant findings or trends observed regarding the mutations and their overall survival impact?

In a group where either 1, 2, or 3 mutations are present, we did find a reasonable number of patients, about 140 patients out of 350 had these changes. We selected a cohort which had testing done, and a result was there. It may not be replicated of all the patients, because there are a lot of patients with missing data so we did not include them, but for the patients where we had this information, it is critical to know that there are quite a bit of patients with these mutations. The concern was that these mutations are at risk for having inferior survival, we did see the same information in the study where the [patients] who had 1 of these mutations had immediate overall survival of 35.8 months compared [with] patients who did not have these mutations. They had a median survival of almost 67 months.

How would you say these findings contribute to the understanding of metastatic prostate cancer biology?

Very critical. This paves the way for future studies or guideline developments. Through our study, through multiple other studies, and through other institutions, we have a strong knowledge base that 1 of these 3 gene mutations at the time of a new diagnosis of prostate cancer is a prognostic marker for poor outcomes. Future clinical trials, some of which are ongoing, should incorporate 1 of these 3 mutations to see if a particular treatment modality would work better or lessen. This way, we can help our patients in future with either treatment intensification if needed. For [patients] who do not have these mutations, could [they] be candidates for treatment deintensification? That way we can improve the outcome of several [patients with] prostate cancer where we use a treatment when needed and hold off if it is not needed.

What are the potential clinical implications of these findings on patient prognosis and treatment decision making?

These changes eventually [will] pave the way for using it as a prognostic marker. One could speculate, and I am using the word speculation because it still has to [happen, but] now, the triplet therapy, which is 1 of the standards –of care for newly diagnosed metastatic castration-sensitive prostate cancer of the combination of androgen deprivation therapy and [androgen receptor pathway inhibitors] along with docetaxel, most patients do not get that. It is specifically reserved for a set of patients with high-volume disease.

The question is, if there are patients where we can segregate this particular group further, where if they do not have any of these mutations, we can avoid chemotherapy, or if there is a group of with lower metastases but has 1 of these alterations, can we intensify the treatment based on these biomarkers? It has implications but still not in clinical practice yet. Clinicians can use this knowledge to risk stratify their patients to see who would benefit [from] triplet therapy or a doublet so that it can give them more information about the patient's prognosis.

Looking ahead, what further research is needed to deepen our understanding of the role of these mutations in metastatic prostate cancer?

There are some studies now utilizing the PTEN pathway to see if we can use specific targeted therapeutics for those patients with these altered genes and see if this can improve their outcomes. There are some new developments, none of them have been completed yet as these are ongoing studies. In the next few years, I think we will see new drug developments addressing these mutations.

Reference

1. Ganiyani MA, Prabhakar P, Khosla AA, et al. Impact of TP53, RB1, and PTEN mutations on overall survival in metastatic prostate cancer: a multi-center study via the Guardian Research Network. J Clin Oncol. 2024;41(4)82. doi:10.1200/JCO.2024.42.4_suppl.82