Correlative Study Identifies Potential Biomarker for Docetaxel Plus ADT in mHSPC

Anis Hamid, MBBS

Anis Hamid, MBBS

Patients with metastatic hormone-sensitive prostate cancer (mHSPC) with a luminal B tumor are associated with better outcomes with the addition of docetaxel chemotherapy to androgen deprivation therapy (ADT) compared with ADT alone. In a correlative study presented at the 2020 Genitourinary Cancers Sumposium (GU 2020), investigators also determined that the basal tumor subtype did not experience as much of a survival benefit with the addition of docetaxel to ADT.

In this analysis, gene expression profiling was conducted on patients from the phase III E3805 CHAARTED clinical trial, in which patients with mHSPC received either ADT alone or in combination with docetaxel. The correlative study was conducted to determine potential biomarkers of response to the combination in this patient population. The primary end point was overall survival (OS), and the secondary end point was time to castration-resistant prostate cancer (TTCRPC).

Out of the 160 patients who underwent profiling, 80 had luminal B tumors (50%), 77 had basal tumors (48%), and 3 patients had luminal A tumors (2%). Patients in the luminal B and basal subtypes had a similar high volume of disease.

The luminal B subtype had a short OS compared with the basal subtype when treated with ADT alone (HR, 1.75;P= .05). In the ADT plus docetaxel arm, patients in the luminal B group demonstrated a significant improvement in OS, as well as TTCRPC, while the basal group did not show benefit with the addition of docetaxel.

The median OS in the luminal B group was 30 months versus 52 months with ADT alone and with the addition of docetaxel, respectively (HR, 0.45;P.007). Median OS in the basal group was 47 months with ADT alone versus 49 months with the addition of docetaxel (HR, 0.85; P= .6). The TTCRPC with ADT alone was 8 months and 6 months compared with 17 months and 18 months in the luminal B (HR, 0.43; P=.43) and basal groups (HR, 0.51; P= .013), respectively.

In an interview withTargeted Oncology, Anis Hamid, MBBS, medical oncologist and genitourinary oncology research fellow at the Dana-Farber Cancer Institute, discussed how the addition of upfront docetaxel to ADT will impact treatment outcomes of patients with mHSPC who have either luminal B or basal tumors. He highlighted the next steps and his own thoughts on the evolution of precision medicine in prostate cancer.

TARGETED ONCOLOGY: Could you provide some background on the CHAARTED trial?

Hamid:The CHAARTED trial was a phase III randomized trial of men with newly diagnosed mHSPC. This trial was reported about 6 years ago, and before that time, the standard of care for men with metastatic disease was androgen deprivation therapy or hormonal therapy. The CHAARTED trial showed that the addition of docetaxel therapy given at the start of diagnosis significantly improved the survival of men with newly diagnosed metastatic prostate cancer.

Since the CHAARTED trial and related trials, such as STAMPEDE and so forth, docetaxel became the standard treatment for men with metastatic prostate cancer. Since that time, a number of different treatments have been introduced in a similar setting, including potent hormonal therapies such as abiraterone, enzalutamide, and apalutamide.

TARGETED ONCOLOGY: What can you tell us about the luminal B subtype?

Hamid:We know a little about luminal and basal subtypes from initial work done in localized nonmetastatic prostate cancer where luminal A, luminal B, and basal subtypes compromised approximately a third each in that population. What we saw with the CHAARTED population in the mHSPC population is that there were few luminal A tumors and most of the tumors were either luminal B or basal.

Luminal B tumors were associated with a shorter survival on hormonal therapy alone. However, that subtype specifically benefited from docetaxel chemotherapy upfront. On the other hand, basal tumors were associated with a relatively better prognosis compared to luminal B tumors, but when we looked at their outcomes with chemotherapy, we didn’t observe a significantly beneficial response to upfront chemotherapy. In this way, it looks like luminal B and basal subtyping not only have prognostic effects but also has a predictive potential.

TARGETED ONCOLOGY: What do you think are next steps?

Hamid:This analysis is interesting, and it has generated a lot of hypotheses and excitement. What is critical is that we take the next step and validate it in independent cohorts. When we develop a biomarker to choose or tailor therapies more precisely for our patients. It’s really important we select biomarkers that have been proven and are reproducible independently. We have collaborated with other groups and other clinical trials that have run similar investigations in this exact disease space to perform similar RNA analyses of their trials in order to test this hypothesis again. We are not quite ready for primetime, but it is giving us some initial insights about the biology.

The second part of that question is we want to dig further into the biology here. We have made some classifications about response and these luminal or basal subtypes, but we need to learn a little bit more about other biological programs and other correlations in place that explain the chemotherapy sensitivity or chemotherapy insensitivity of these disease subtypes.

TARGETED ONCOLOGY: Are there other therapies that may be showing benefit for the luminal B subtype?

Hamid:We know that the luminal B subtype appears to benefit from docetaxel. One of the important questions is whether these luminal B and basal subtypes respond similarly with potent hormonal therapies that we have in clinic, such as abiraterone, enzalutamide, or apalutamide. Luckily, we are partnered with trials that have tested these drugs in a prospective setting, and hopefully, we will learn once we have more information from the RNA profiling of those studies.

TARGETED ONCOLOGY: Are there any other unanswered questions that you hope to answer in the near future?

Hamid:In terms of the development of a more precise way of mHSPC, the data we have at this stage is only related to gene expression profiling, which is what was been presented at the symposium. We want to know other ways of biological information, namely what is happening with the tumor genomics, what are the mutational characteristics of these tumors that may be affecting prognosis, or the predictive effects that we hypothesize there are with certain genomic alterations. There are layers of biological information about genomics, such is epi-genomics, and how, for example how demethylation might affect treatment response and prognosis. What we are hoping to do is integrate multiple layers of biological information across independent cohorts to get a more multi-dimensional view of the biomarkers that might guide precision care for these patients.

TARGETED ONCOLOGY: What is it like to see these precision medicine developments make a lot more headway in prostate cancer?

Hamid:It is exciting to see precision medicine being translated to prostate cancer. We have always known that, for example in the case of chemotherapy, there are certain sub-populations of patients that benefit and sub-populations of patients that do not. We have tested this in ways that are more clinically driven, like volume of metastatic disease, but almost certainly there will be biological parameters that can guide our treatment decisions better to hopefully make our decision more precise.

This is the way that oncology is moving across the board. We are refining the way we treat patients and approach different therapies being informed by not only the clinical information we have but also the biological information and drug response information, and [other details]. It is all in the view of getting the best therapies to patients that are going to have a benefit from it and finding better therapies for patients who are not predicted to benefit from those particular drugs.

Reference:

Hamid A, Wang XV, Chen YH, et al. Luminal B subtype as a predictive biomarker of docetaxel benefit for newly diagnosed metastatic hormone senstivie prostate cancer (MHSPC): A correlative study of E3805 CHAARTED [Published Online].J Clin Oncol.doi: 10.1200/JCO.2020.38.6_suppl.162.