The Impact of MDT on Intermittent Hormone Therapy: Insights from the EXTEND Trial, Journal Club - Rashid Sayyid & Zachary Klaassen

June 8, 2023

Rashid Sayyid and Zach Klaassen dissect the findings of the EXTEND trial, a phase two randomized study focused on the effects of adding metastasis-directed therapy (MDT) to intermittent hormone therapy for oligometastatic prostate cancer. As per the JAMA Oncology published report, despite evidence supporting systemic therapy intensification for metastatic prostate cancer, the combination of MDT and hormone therapy hadn't been evaluated until now. The EXTEND trial, investigating 12 distinct solid tumor types, revealed that MDT in combination with hormone therapy improves progression-free survival and modulates immune response in patients with oligometastatic prostate cancer. The researchers also highlight the study's limitations, such as accruing prior to the routine use of PSMA PET/CT scan, but consider its results significant in terms of enhanced treatment outcomes and minimized duration of medical castration.


Rashid Sayyid, MD, MSc, Urologic Oncology Fellow, Division of Urology, University of Toronto, Toronto, Ontario

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center

Read the Full Video Transcript

Rashid Sayyid: Hello everyone. This is Rashid Sayyid. I'm an Urologic Oncology Fellow at the University of Toronto and along with Dr. Zach Klaassen, Assistant Professor and Program Director at Augusta University, we'll be discussing the recently published EXTEND trial, which was a phase two randomized trial that looked at the addition of metastasis directed therapy to intermittent hormone therapy for oligometastatic prostate cancer. This study was recently published in JAMA Oncology. So we know that there's strong evidence for upfront systemic therapy intensification for metastatic prostate cancer with current guidelines recommending upfront hormone therapy irrespective of disease volume. MDT or metastasis directed therapy in oligometastatic prostate cancer in lieu of upfront systemic therapy has been evaluated in two phase two trials of note, the ORIOLE trial, which identified oligometastatic disease based on conventional imaging and the STOP trial, which used choline PET for that purpose. Recently published pooled data by Deek et al. JCO 2022 showed that MDT in this setting without hormone therapy prolonged time to androgen deprivation therapy and improved progression-free survival from six to 12 months.

Noticeably, however, there was no improvement in radiographic progression free survival, time to castrate resistant disease, or overall survival. Surprisingly, the combination of MDT and hormone therapy has yet to be evaluated in the study from RCT despite the fact that hormone therapy and MDT are commonly used together in clinical practice and there's strong preclinical and clinical evidence for synergy between the two modalities. So the study objective of EXTEND was to evaluate whether MDT addition to hormone therapy in oligometastatic prostate cancer patients improves progression-free survival, prolongs time from testosterone recovery to disease progression, the so-called eugonadal progression-free survival, and whether this combination modulates peripheral T-cell immune subset distribution and receptor expression. Of note, intermittent hormone therapy as opposed to continuous therapy was chosen due to the indolent nature of oligometastatic prostate cancer, the ability of metastasis directed therapy to defer systemic therapy, and the thought that intermittent therapy could induce synergy with MDT while theoretically minimizing castration side effects.

So the EXTEND trial was a phase two investigator initiated controlled open-label multicenter basket RCT, and this trial was intended to evaluate whether MDT addition to standard systemic therapy improves progression-free survival across 12 distinct solid tumor types. So this wasn't only for prostate cancer, but in this trial or in this study, we'll discuss the prostate cancer basket. Between September 2018 and November 2020, patients who were 18 years of age or older with ECOG performance status of zero to two was less than or equal to five metastatic sites were amenable to MDT. So again, there's been a decent amount of debate about what defines oligometastatic disease. Some studies have used definition of three, others have used five, in this study they've used five or less. And once the pre-specified number of events was reached, 41 in this study, results from the prostate intermittent hormone therapy basket were analyzed.

In this next slide, we see the study design for EXTEND. Again, the major inclusion criteria where histologic diagnosis of prostate cancer with five or less metastases. It's important to note that one of the eligibility criteria was a receipt of at least two months of prior hormone therapy, either a GNRH agonist or antagonist plus or minus a second generation hormone therapy such as abi, enza, et cetera. Of note, untreated primaries were allowed, however, if patients had not received treatment to the prostate before, they received external beam radiation therapy to the prostate consistent with the current standard of care. If we look at the study design here, we included oligometastatic prostate cancer patients and these were randomized to the experimental arm of combination therapy with MDT and six months of hormone therapy or hormone therapy alone, which was six months. At six months, all patients received a hormone therapy break and then hormone therapy in either arm was resumed at the first sign of progression made by a chemical radiographic or clinical.

All patients received baseline imaging and it's important to note this wasn't PET detected. This was using conventional imaging for the most part. All patients received CT chest, abdomen, and pelvis with contrast and a bone scan, and a subset did receive the Axumin scan of the fluciclovine F18 PET/CT. It's important to note that all metastatic lesions present before hormone therapy were treated with MDT and this included any lesions that emerged during hormone therapy. PSA was checked every 12 weeks for the first two years, followed by every 18 weeks thereafter, and imaging was repeated when PSA increased by one or at the time of disease progression. The primary endpoint was progression-free survival, which is defined as the time from randomization to either radiographic, clinical, or biochemical progression. Biochemical progression was defined as PSA increased by 25% or more, or two nanograms per ML above nadir.

Secondary endpoints include eugonadal progression-free survival, and that was from the time testosterone level reach 150, overall survival time to subsequent systemic therapy, time to appearance, immune lesions, time to local treatment failure. They looked at safety outcomes and they specifically looked at those that were graded at two or worse. They looked at quality of life metrics and importantly they looked at peripheral blood samples for analyzing immune cell subsets and T-cell receptors that were collected at baseline and first follow up. The primary analysis cutoff date was January 7th, 2022, and this study was designed with an 80% power to detect a median PFS improvement from 18 to 36 months using a one-sided log-rank test with a type one error of 10%. The used standard survival analysis metrics using the Kaplan Meier log-rank and the Cox proportional hazards model to adjust for covariates of interest and given the repeated measurement nature of the quality of life metrics and the same patients over time, they analyze this using the linear mixed models. And at this point I'll turn it over to Zach to discuss the results and the discussion.

Zachary Klaassen: Thanks so much for that great introduction, Rashid. So this is the CONSORT diagram for the EXTEND trial. So there was 124 patients that were assessed for eligibility. Ultimately, 87 men were randomized including 43 to the combined therapy arm and 44 to the hormone therapy alone arm. This is the baseline characteristics. As you can see here, this was a rather large table, so I split it into two panels for easier viewership. As we can see on the right is hormone therapy alone to the left of the column is combined therapy. The median age was well-balanced between these two groups at 67 years. Overall, roughly 77% of patients in the combined arm were white compared to 89% in the hormone therapy arm. And we look at prior local treatment to the prostate, roughly 60% in the combined therapy arm had surgery compared to 48% in the hormone therapy arm. And 12% had radiation in the combined therapy arm compared to 18% in the hormone therapy arm. Overwhelmingly, the majority of these patients were castrate sensitive, over 90% in both arms.

The most common stage at enrollment was M1b at roughly two thirds in both groups. Second most common was M1a at roughly one quarter of the patients. And we look at duration of hormone use before randomization. This is relatively well-balanced between the two groups. You see the most common timeframe was four to 12 months of hormone prior to randomization, 58% in the combined therapy arm and 50% in the hormone therapy arm. Moving to the right panel, prior lines of systemic therapy, majority of these patients were completely untreated, at roughly 70% in both arms. PSA level enrollment, majority of patients had a PSA of less than two. In terms of metastatic lesions, we see metastatic lesions of one in 28% combined hormone therapy and 48% hormone therapy alone. Two lesions, 42% combined therapy, 30% hormone therapy alone. There was several patients, five patients in the combined therapy arm and six in the hormone therapy alone arm, that had four to five metastatic lesions. As Rashid mentioned, CT and bone scan was the most common modality, roughly three quarters with about one quarter of the patients receiving Fluciclovine PET/CT.

In terms of second generation anti-androgens, majority of these patients had no prior anti-androgen use, although roughly one third of patients did have abiraterone. The primary outcome, as Rashid mentioned, was progression-free survival over median follow-up of 22 months. The median PFS for combined therapy was not reached and for hormone therapy alone was 15.8 months. And you can see with the early and wide separation of the curves, this favored the combined therapy arm hazard ratio of 0.25, 95% confidence interval of 0.12 to 0.55. The key secondary outcome was eugonadal PFS. Again, early and wide separation of the curves, the median PFS for the combined therapy arm was not reached, whereas for the hormone therapy arm it was 6.1 months with a hazard ratio of favoring combined therapy of 0.32 and 95% confidence interval of 0.11 to 0.91.

This is a force plot looking at key patient subgroups for PFS. To the left favors combined therapy, to the right favors hormone therapy alone. And we can see that among all these subgroups there was a benefit for improvement in combined therapy. We do see that several of these were not quite statistically significant, namely PSA greater than 0.2, N1 or M1a disease, no prior primary therapy and metastatic lesions numbering three to five. But generally there was a benefit to all of these groups for combined therapy. This figure looks at the duration of testosterone states by randomization arm and so I'll walk you through this figure. Basically zero is a randomization, to the left is before randomization, to the right is after randomization. The top half of this figure looks at combined therapy, whereas the bottom half looks at hormone therapy only. First, we'll look at receipt of hormone therapy, which is in dark blue.

And just generally looking at this, we see that there was relative balance between these two arms with regards to receipt of hormone therapy before randomization as well as after randomization. In slightly lighter blue, hormone therapy cessation, we see that this was a little bit more prominent in the combined therapy arm compared to hormone therapy alone and we certainly see more eugonadal testosterone level in the combined therapy arm compared to hormone therapy only. Again, looking at progressive disease, at least qualitatively we see that the hormone therapy only arm had more progressive disease compared to the combined therapy arm. This figure looks at the immune cell subset sets and T-cell receptor sequencing. On the left is changes in CD4 and CD8 positive T-cell subpopulations. And basically the take home message from the left hand of the slide is that in the combined therapy arm there was increased CD4 and CD8 positive T-cells with high and intermediate KI-67 expression and program cell death protein 1 expression at the time of follow up.

On the right is the numbers of expanded and contracted TCR clones. And the take home message from this side of the panel is that in the combined therapy arm, higher numbers of expanded and contracted TCR clones were seen at first follow up, which suggests that greater T-cell clonotype modifications in the combined therapy arm. With regards to adverse events, generally this is well-balanced between these two groups and generally very few grade two and grade three adverse events, only 16 total grade two and only six total grade three. And amongst these specific adverse events, there was no difference between the two arms. Again, across several quality of life metrics including SF-12 mental, SF-12 physical, we see that there was no difference between the combined therapy arm and the hormonal therapy arm with regards to quality of life. So by way of discussion, the EXTEND trial found that the addition of MDT to intermediate hormone therapy improved PFS and the key secondary endpoint of eugonadal PFS.

Since all men resumed hormone therapy at the time of progression, metastasis directed therapy facilitated a longer time with eugonadal testosterone as part of an intermittent hormone therapy strategy. As we just discussed, adverse events were modest with no difference in grade three or greater toxic effects or quality of life measurements between these two arms. There's several key differences between the EXTEND trial and the STOMP and ORIOLE trials. The first is that EXTEND was the only trial to incorporate hormone therapy and was also the first trial to assess intermittent hormonal therapy in the setting of oligometastatic prostate cancer. Secondly, EXTEND enrolled men with previously untreated primary prostate cancer, men receiving novel hormonal therapy, men with castrate resistant disease, and men with up to five sites of metastatic disease. So it was a much more all-comer trial than the previous two published trials.

One of the key limitations of this study, as Rashid mentioned in the introduction, is that the study accrued before the routine use of PSMA PET/CT scan. So in conclusion, in the EXTEND phase two randomized clinical trial, PFS was significantly improved with the combination of MDT and hormone therapy versus hormone therapy alone for all oligometastatic prostate cancer. These results support the safety and effectiveness of adding MDT to intermittent hormone therapy to prolong cessation of hormone therapy in men with oligometastatic disease. And finally, this strategy leveraged the non-invasiveness of radiation and hormone therapy to enhance the radiation benefit while limiting the duration of medical castration. We thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussing the recently published extend trial in JAMA Oncology.