ASCO 2023: When More Is More: Treatment Intensification for Hormone-Sensitive Prostate Cancer

(UroToday.com) The 2023 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL between June 2^nd and June 6^th was host to a session on prioritizing and sequencing therapy for advanced prostate cancer. Dr. Neeraj Agarwal discussed the current treatment landscape of metastatic hormone-sensitive prostate cancer (mHSPC), debating in favor of early treatment intensification for mHSPC patients and arguing that ‘more is more’ in this scenario.

Over the last decade, we have seen numerous agents approved in the mHSPC disease space in combination with ADT. involving treatment for hormone sensitive prostate cancer
Starting with CHAARTED, this was the first trial to demonstrate an overall survival (OS) improvement with ADT intensification. The addition of docetaxel to ADT prolonged OS in men with mHSPC, with an improvement in median OS from 57.6 to 44 months (HR: 0.61, 95% CI: 0.57 – 0.80, p<0.001).¹

Hazard ratio chart
This was followed by numerous trials in this disease space that demonstrated that the addition of an androgen receptor pathway inhibitor (ARPI) to ADT significantly improved OS, as summarized in the slide below. He highlighted that all these trials of doublet therapy combinations of ADT + an ARPI demonstrated similar OS improvement, with OS rate reductions of 30-35% across all these trials. Even more impressively, these improvements were, for the most part, consistent across all evaluable subgroups, including those across disease presentation (synchronous versus metachronous, volume (low versus high), Gleason score, PSA, and age, with the exception of visceral metastases (lower reponse), which were present in approximately 10% of trial patients in the mHSPC setting.
doublet therapy trial table
More recently, we have had two trials of triplet therapy combinations that have demonstrated an overall survival benefit with ADT + docetaxel + either abiraterone (PEACE-1)¹ or darolutamide (ARASENS).² overall population

abi group graph
Similar to the ARPI doublet therapy trials, consistent benefits were seen across subgroups with these triplet therapy regimens, with the exception of metachronous disease in the ARASENS trial and low-volume patients in the PEACE-1 trial, which included patients with de novo disease only. triplet trial table
The results of these trials have been reflected in the most recent update of the NCCN prostate cancer guidelines of 2023. For patients with mHSPC, ADT + ARPI doublet or triplet therapy combinations with additional docetaxel are now considered standard of care treatments.
NCCN guideline info
But despite the high-level evidence with wide-spread endorsement from numerous guidelines, are these recommendations being translated into real-world practice? What are the treatment patterns in the real world? Real-world analysis across various settings, including academic or community-based practices and population-level data using SEER-Medicare, have all consistently demonstrated that a significant proportion of mHSPC patients do not receive early treatment intensification, irrespective of whether these patients were treated by medical oncologists, urologists, or radiation oncologists. study evaluation table
This issue is further exacerbation among African American or Black patients who are even less likely to receive treatment intensification in this setting. trial implementation for minorities
But is this limited to the United States or is this a global issue? A study published by Dr. Pedro Barata recently demonstrated that approximately 40% of mHSPC patients do not receive treatment intensification and that this issue is not limited to the United States, with similar trends seen in other notable European countries, including the UK, France, Germany, Spain, and Italy. Furthermore, docetaxel was uncommonly used with <10% of US patients receiving docetaxel in this setting, compared to <30% of patients from the European countries.⁴ trend toward increasing intensification of treatment
It appears that urologists and medical oncologists are both equally responsible for this clinical implementation gap. Can we identify reasons for this? Based on work by Dr. Freedland presented at ASCO GU 2022, it appears that the reasons are as follows: decline intensified adt Potential solutions to bridge this implementation gap, include:

Improving education among providers via:
- Digital media (e.g., Twitter)
- Hybrid conferences and webinars
Incorporating artificial intelligence-based decision-making tools to electronic medical records

What are our patients’ priorities in this setting? A study by Oswald et al. demonstrated that only 32% of patients strongly agreed with the sentiment of “I need to live as long as possible, no matter how I feel, so that I can take care of my loved one”. This highlights the importance of outcomes other than just OS for our patients. Furthermore, 21% of patients do not solely rely on physicians to treat their prostate cancer, highlighting the importance of patient-level input for shared decision-making and disease management.
Partnering with patients
This highlights the importance of further educating our patients, with potential solutions including:

Open-access patient-friendly publications
Conference talks and webinars addressed exclusively to patients
Open-access websites

patient education and assistance
Another issue to consider is the financial aspect, with 26% and 20% of physicians stating that lack of reimbursement and patient financial constraints were the main barriers to treatment intensification. This is a significant concern given that ADT monotherapy on average costs $165 out of pocket per the first year of treatment, compared to $4,236 for an ARPI. In this domain, we need to consider insurance companies, healthcare institutions, and pharmaceutical companies.

In an effort to tackle out of pocket costs, legislative acts are the main focus. The Inflation Reduction Act will lower prescription drug prices in Medicare through price negotiations with manufactures, implement a yearly cap of $2,000 in 2025 on out-of-pocket prescription drug costs in Medicare, and continue to lower health insurance premiums through HealthCare.gov and the state-based marketplaces. But out of pocket expenses is only one aspect of the financial toxicity, and we need advocacy at the highest level to change health policies and potentially improve patient outcomes. One important advocacy issue is the HELP Copay Act’s attempt to ban the Co-Pay Accumulator Program, which prevents patient assistance funds from being applied towards a patient’s annual out-of-pocket maximum or deductible. patient advocacy
Another important target of advocacy efforts is to improve access via addressing prior authorization burdens, which are associated with:

Delays in treatment and diagnostic imaging
Patients being forced onto a second-choice therapy or denial of therapy altogether
Increased out-of-pocket patient costs

Shifting gears back to the NCCN guidelines, Dr. Agarwal noted that both ARPI-based doublet therapies and triplet therapies are recommended in this setting. Why is that? To date, there are no randomized controlled trials comparing triplet therapies to ARPI-based double therapies (doublet: ADT + docetaxel in ARASENS and PEACE-1). As such, can we rely on biomarkers to decide on treatment intensification? One such biomarker may be PSA levels within 6 months of initiating therapy. Those who fail to achieve a PSA <0.1 ng/ml, and thus having worse prognoses, may be more suitable for a personalized treatment escalation approach with the addition of docetaxel. personalizing adt intensification
Genomic biomarkers in this setting may include:

SPOP mutations, with patients having such mutations not deriving added benefit from docetaxel addition Administer ADT+ ARPI only?
PTEN/RB1/TP53 loss, with such tumors in the mCRPC setting being less androgen sensitive Consider adding docetaxel in this setting

Current ongoing biomarker-driven, phase 3 trials in the mHSPC disease space include:

TALAPRO-3:
- ADT + enzalutamide +/- talazoparib in DDR positive tumors
AMPLITUDE
- ADT+ abiraterone +/- niraparib in patients with HRR gene mutations
CAPItello-281
- ADT + abiraterone +/- capivasertib in PTEN deficient tumors
PSMAddition
- SOC +/- ¹⁷⁷Lu-PSMA-617 in patients with PSMA-positive disease

TALAPRO AMPLITUDE
Dr. Agarwal shared his vision for the future of mHSPC treatment, as summarized below: future of treatment for mHSPC
Dr. Agarwal concluded his presentation as follows:

There is no role for ADT alone for mHSPC patients, except in select circumstances (e.g., life expectancy <2 years)
Doublets of ADT + ARPI are applicable to most patients, with the exception of those with visceral metastasis or other high-risk genomic or clinical features
There is no role for ADT + docetaxel doublet anymore, given the superiority of triplet regimens of ADT + docetaxel + an ARPI compared to doublets of ADT+ docetaxel (PEACE-1 and ARASENS)
There is a need for partnerships with patients to improve awareness and access to allow “more treatment”
Advocacy is essential to improving access to care and bridging the implementation gap
Further biomarkers in this space are needed, but the “art” of medicine is more important than ever.

Presented by: Neeraj Agarwal, MD, Professor, Department of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.

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