(UroToday.com) The 37th Annual European Association of Urology Congress held in Amsterdam, Netherlands between July 1st, and 4th 2022 was host to a session about the management of metastatic hormone-sensitive prostate cancer (mHSPC). Dr. Eleni Efstathiou was tasked with arguing in favor of systemic combination therapy in the management of de novo metastatic hormone-sensitive prostate cancer (mHSPC) in patients with oligometastatic disease (cT3N+M1a).
Dr. Heidegger began this discussion with a case presentation of a 57-year-old patient with de novo mHSPC (low risk per LATITUDE/low volume per CHAARTED):
-PSA level= 81 ng/ml
-Grade Group two disease in 7/15 cores
-cT3N+M1a disease (1 para-aortic, left iliac and left retroperitoneal enlarged node)
-Otherwise, healthy with no comorbidities, not on any regular medications and asymptomatic
-Patient was started on apalutamide 240 mg/d with subsequent PSA suppression <0.03 ng/ml after 3 months of therapy and complete radiologic response on surveillance PSMA-PET/CT imaging.
Dr. Heidegger left the presenters with the following questions:
- What is “the best” systemic treatment for this patient?
- What is the impact of radiotherapy to the primary tumor in this patient?
- What is the impact of triplet therapy in this patient?
- Should we offer targeted therapy of the primary lesion and metastatic sites?
Dr. Efstathiou began her presentation by noting how far along we have come in the management of mHSPC since 2014. It was not that long ago that we were debating the appropriate ADT regimen for mHSPC. She referenced Dr. Maha Hussain’s seminal work from 2013 that demonstrated that continuous ADT conferred superior median OS rates compared to patients treated with intermittent therapy (5.8 versus 5.1 years, HR: 1.09, 95% CI: 0.95 – 1.24).1
The requirements for outcomes to be truly “practice changing” are:
- Addressing unmet need(s)
- Study design that compares the experimental arm to a ‘standard’ practice
- Positive outcomes that are clinically meaningful
- Reproducible results
- Practices accessible to the community
- New standard of care improves “therapeutic index” in real world practice, in terms of efficacy and safety
Dr. Efstathiou strongly believes that androgen signaling inhibition study outcomes to date meet all such criteria.
Tremendous progress has been made in the mHSPC space with regards to use of second-generation antiandrogens starting with LATITUDE (abiraterone) presented at ASCO 2017 to ARASENS (darolutamide) presented most recently at ASCO GU 2022.
These trials have not only taught us that combination treatment is superior, but that earlier treatment, specifically, is associated with improved outcomes.
Dr. Efstathiou next referenced a study from 2017 by Abida et al. that demonstrated an increase in mutation frequency and copy number alterations with more advanced stage disease, specifically with regards to DNA damage repair (DDR), PI3K, and MAP kinase pathways.2 Dr. Efstathiou next wondered are we treating these patients appropriately timely and wisely, or out lack of understanding?
Dr. Efstathiou highlighted the importance of germline testing in these patients, which has been reinforced by the most recent EAU, ESMO and NCCN guidelines.
The challenge in this disease space remains: how do we maximize the “therapeutic index” by offering our patients treatment regimens with the most efficacy, while minimizing the toxicity profile. This is of special relevance with the emergence of triplet therapy in the PEACE and ARASENS trials. The key remains to identify the subset of patients who are most likely to benefit a specific treatment modality. This is exemplified by radiation therapy use, which has a diminishing therapeutic index when utilized across a disease spectrum from localized prostate cancer to oligometastatic disease to high volume metastasis. Conversely, systemic therapy with ADT has a rising therapeutic index along the same disease continuum.
To conclude, Dr. Efstathiou asked: How do we maximize the therapeutic index based on available data and in the absence of predictors for this “young” patient with oligometastatic mHSPC? When considering that two of three published Docetaxel trials in this setting STAMPEDE, CHAARTED) and seven out of seven androgen signaling inhibitor trials (LATITUDE, STAMPEDE, ARCHES, ENZAMET, TITAN, PEACE-1, ARASENS) have been positive trials, Dr. Efstathiou listed her four take home messages:
- Combination of ADT with enhance androgen signaling inhibition is a requirement for the vast majority of mHSPC with consistent monitoring
- Combination should initiate at diagnosis and not be delayed
- Oligometastatic disease warrants treatment of primary
- Consider germline testing
The questions remain: What is the role of metastasis directed therapy in the setting of oligometastatic disease? And if so, when do we stop systemic treatment?
Presented by: Dr. Eleni Efstathiou, MD, PhD, Associate Professor, Genitourinary Oncology Section Chief, Houston Methodist Cancer Center, Houston, TX
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2022 European Association of Urology (EAU) Annual Hybrid Meeting, Amsterdam, NL, Fri, July 1 – Mon, July 4, 2022.
References:
- Hussain M, et al. Intermittent versus continuous androgen deprivation in prostate cancer. 2013. N Engl J Med;368(14):1314-25.
- Abida W, et al. Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making. JCO Precis Oncol. 2017;2017:PO.17.00029.