APCCC 2021: Do Different Subgroup of Patients Need Different Treatments?

(UroToday.com) The first session of the Advanced Prostate Cancer Consensus Conference 2021 which was hosted in the context of the COVID-19 pandemic focused on the management of patients with newly diagnosed metastatic hormone-sensitive prostate cancer. Following presentations from Dr. Karim Fizazi and Dr. Ian Davis focusing on the evidence for “triplet therapy” based on intensification of initial androgen deprivation therapy, Dr. Chris Sweeney discussed the question of how we may personalize care and provide different treatment approaches to different subgroups of patients.

He began by highlighting the importance of considering patient-, cancer-, and biology-level features when we considering personalizing treatment decision in metastatic castration sensitive prostate cancer (mCSPC). At the patient-level, we should consider patient preferences, along with expected lifespan, comorbidities, frailty, access, and safety. In particular, in the context of the COVID-19 pandemic, he emphasized that local pandemic related considerations may affect the decision to recommend chemotherapy, with its associated immunosuppression. At the cancer-level, he emphasized that we need to consider the underlying prognosis as dictated by synchronous versus metachronous presentation and extent of metastasis. Finally, considering biologic prognostication, he highlighted that this is an active area of investigation and, as of today, doesn’t directly influence treatment decisions in clinic for the most part.

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The whole premise of this talk is predicated on the hypothesis that men with mCSPC may have a wide array of prognoses which: (1) may be easily defined based on clinical characteristics, (2) impacts the efficacy of different treatment strategies, and (3) each prognostic group has a unique underlying biology.

He emphasized that, to date, mCSPC prognostic groups have been based on the number and distribution of metastases. While there are a number of groups that have assessed this including SWOG, MDACC, CHAARTED, and LATITUDE, Dr. Sweeney emphasized that regardless of definition, patients with poor risk or high-volume disease do poorly compared to good risk patients. Further, across definitions, there are relatively comparable overall survival for those deemed as having poor risk or high-volume disease.

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Dr. Sweeney emphasized that, beyond these definitions of poor risk or high-volume disease, synchronous versus metachronous presentations meaningfully affect treatment outcomes. Focusing on patients who received testosterone suppression alone, he emphasized that (among patients with low-volume disease) patients with metachronous metastases had substantially longer median overall survival (~ 8 years) compared to those with de novo metastasis (~4.5 years). While the magnitude of effect was smaller (~4.5 years among those with metachronous versus ~3 years among those with de novo disease), a similar effect was observed among those with high-volume disease.

Dr. Sweeney then discussed two extremes of clinical presentations in mCSPC, ranging from a young, healthy man with a high-volume of synchronous metastatic disease to an older, comorbid man with low-volume disease many years following local therapy. Clearly, these men have a different potential to benefit from treatment.

Examining first data for the use of docetaxel, Dr. Sweeney emphasized that we may be confident in its benefit for patients with high-volume disease whether de novo or metachronous. However, the benefit of docetaxel is substantially less clear for patients with low volume de novo disease and its is almost certainly not beneficial among those with low volume metachronous disease, as highlighted in the table below summarizing three randomized controlled trials in this disease space.

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He then moved to the question of the role of local prostate radiotherapy. Unlike the somewhat conflicting results between trials of docetaxel in low-volume disease, the benefit of radiotherapy among patients with low-volume disease is relatively consistent in the two trials which assessed this question. Thus, if choosing between radiotherapy and docetaxel in patients with low volume disease, Dr. Sweeney emphasized that he prefers radiotherapy.

Dr. Sweeney then moved to discussing the use of novel androgen receptor targeting agents. Unlike docetaxel, there is a relatively consistent benefit of the addition of these agents, across disease groups defined based on volume and timing.

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In addition to the stronger, more consistent signal evidenced here, Dr. Sweeney also highlighted that these data show a benefit for the addition of novel androgen receptor targeting agents in patients with metachronous metastatic disease. This question was further assessed in a pooled analysis of TITAN and ENZAMET emphasizing that there is a significant survival benefit in this population (HR 0.46) with an even greater benefit among those with low-volume metachronous disease (HR 0.40). In this subgroup, Dr. Sweeney emphasized that we need data to assess the role of stereotactic body radiotherapy (SBRT) to metastatic sites to understand whether this improves outcomes.

Summarizing available data, Dr. Sweeney emphasized that there is substantial data available regarding the question of testosterone suppression and docetaxel with or without novel androgen receptor inhibitors. The signal among patients who have received prior docetaxel (based on TITAN and ARCHES) is somewhat unclear. In terms of concurrent therapy (based on PEACE-1 and ENZAMET), the data is mixed with evidence from PEACE-1 demonstrating an overall survival benefit in those with high-volume disease with an unclear signal (and immature data) from ENZAMET.

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Moving to specific patient subgroups, Dr. Sweeney emphasized potential differences in terms of disease biology based on phenotypes. He highlighted the particular importance of liver metastases. While there is evidence of benefit for the use of docetaxel in these patients, the benefit of novel androgen inhibitors in somewhat unclear. Further, these data are muddied by the aggregation of “visceral” disease to include lung, liver, adrenal, and other sites in some studies despite the fact that the biology and prognosis of these sites may differ. Building off this principle, he highlighted that emerging work has demonstrated that mutation frequency may differ according to clinical presentation.

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In closing, Dr. Sweeney emphasized that we may consider differing treatment approaches according to patient presentation as characterized by timing (metachronous vs synchronous metastases) and distribution (volume and involvement of visceral disease).

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Presented by: Christopher Sweeney, MBBS, Professor of Medicine, Harvard Medical School, Dana Farber Cancer Institute.

Written by: Christopher J.D. Wallis, University of Toronto Twitter: @WallisCJD during the 2021 Advanced Prostate Cancer Consensus Conference, Saturday, October 9, 2021.

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