(UroToday.com) The 2024 American Urological Association (AUA) Annual Meeting held in San Antonio, TX between May 3rd and 6th, 2024 was host to the International Prostate Forum. Dr. Paul Sieber discussed optimizing combination therapy for patients with metastatic hormone-sensitive prostate cancer (mHSPC).
He noted that all current guidelines are in consensus agreement that doublet therapy with androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI) is the recommended approach for mHSPC patients, irrespective of disease volume.
How do we stage these patients? Trials in this space have relied on findings from conventional imaging. However, there is clearly a growing role for PSMA-PET/CT with current guidelines endorsing its role, as follows:
- AUA: “Clinicians should utilize PSMA PET imaging preferentially”
- EAU: “Treatment should not be changed based on PSMA PET/CT findings, in view of current available data”
- NCCN: “PSMA-PET/CT or PET/MRI can be considered as an alternative to standard imaging of bone and soft tissue for initial staging”
Although PSMA has demonstrated improved diagnostic performance characteristics for staging prostate cancer patients, numerous limitations remain. Not all lesions express PSMA on their cell surface and, thus, are not PSMA avid. There may be a complementary role for FDG PET in this setting to identify those patients with aggressive variant prostate cancer. Currently, there is no standardized, validated approach to identifying these patients clinically, with the following parameters used in aggregate to help parse out this aggressive variant subgroup:
- Small cell prostate cancer
- Lytic bone lesions
- Bulky lymphadenopathy
- PSA <10 with high-volume bone disease
- Hypercalcemia
- Elevated LDH
- Elevated CEA
- Genomic alterations in PTEN, RB, and TP53
Next, Dr. Sieber addressed the role of triplet therapy with ADT + an androgen receptor pathway inhibitor (ARPI) + docetaxel. What do the current guidelines recommend regarding triplet therapy:
- AUA: “In selected patients with de novo mHSPC, clinicians should offer ADT in combination with docetaxel and either abiraterone acetate plus prednisone or darolutamide”
- EAU: “The choice will most likely be driven by fitness for docetaxel, the nature of the disease (low/high volume, synchronous/metachronous), patient preference, the specific side effects, availability, logistics, and cost.”
- NCCN: “Patients with high-volume castration-sensitive metastatic prostate cancer who are fit for chemotherapy should be considered for triplet therapy”
What tools available can we use to help decide which patients could benefit from triplet therapy? Numerous risk stratification tools exist, including D’Amico, NCCN, and CAPRA that rely on a combination of widely available clinicopathologic variables, including PSA, Gleason Score, and clinical stage, among others. Dr. Sieber noted that additional variables of particular interest include:
- Age
- Performance status
- Disease timing (synchronous versus metachronous)
- Genomic profiling
- Site of metastasis
- The site of metastasis has implications, as does disease volume. High volume, as per the CHAARTED definition, is acknowledged as a criterion for consideration of triplet therapy in the EAU and NCCN guidelines.
What is the role of genomics in this setting? The AUA and NCCN both discuss germline and somatic genomic testing and specifically note that it “may be used for treatment decision-making”. BRCA is the most common mutation and is strongly prognostic of worse cancer survival outcomes. Overall, the presence of any homologous recombination repair (HRR) mutations portends worse survival outcomes. In addition to HRR mutations, other genomic findings of interest include:
- SPOP (speckled type POV protein) mutations: Enhances sensitivity to ARPIs, not docetaxel
- PTEN, RB, or TP53 loss
Other important variables to consider when deciding on treatment intensification include age, frailty, and cardiac status:
What about the role of radiation therapy for low-volume mHSPC?
- EAU: "Offer ADT combined with non-curative prostate radiotherapy (using doses up to the equivalent of 72 Gy in 2 Gy fractions) to patients whose first presentation is M1 disease and who have low volume of disease by CHAARTED criteria/M1a disease. Do not offer ADT combined with any local treatment (RT/surgery) to patients with high-volume (CHAARTED criteria) M1 disease outside of clinical trials (except for symptom control)".
- NCCN: "RT to the prostate should be considered in patients with lower metastatic burden castration-sensitive metastatic disease according to conventional imaging when added to ADT."
- AUA: " In selected mHSPC patients with low-volume metastatic disease, clinicians may offer primary radiotherapy to the prostate in combination with ADT(Grade C)
In summary, Dr. Sieber noted that:
- Triplet therapy (versus doublet therapy) for mHSPC patients should only be considered in high-volume, fit patients, accounting for other clinicopathologic variables
- Consider radiation therapy addition to dual therapy in conventional imaging-defined low-volume mHSPC
Presented by: Paul Sieber, MD, Medical Director for Clinical Trials, Keystone Urology, Lancaster, PA
Written by: Rashid Sayyid, MD, MSc - Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 American Urological Association (AUA) Annual Meeting, San Antonio, TX, May 3rd - 6th, 2024