Episode 089: Prostate Cancer Series, Pt. 6- Treatment for Met. Castrate Sensitive Prostate Cancer

Written By TheFellowOnCall HemeOncPodcast

This week, we continue our discussion about metastatic castrate sensitive prostate cancer. Spoiler alert: there is not good guidance or biomarkers that help us pick one regimen over another. In this episode, we go through the data, our critical appraisal of the data, and some things to consider when selecting one regimen over another. 

As a refresher, be sure to check out our Pharmacology Episode and our introductory episodes, as we will be building on these concepts. 

Important considerations when approaching metastatic disease

  • Is this castration sensitive or castration resistant metastatic disease?

  • Is this high volume or low volume metastatic disease?

    • High volume defined as (based on CHAARTED trial)

      • Presence of visceral metastases or

      • 4 or more bone mets with one beyond the vertebral bodies and pelvis

    • The distinction is critically important when we think about when to incorporate triplet therapy with something like ADT + docetaxel + abiraterone with prednisone 

Who should be tested for germline genetics (BRCA Testing)?

  • Check germline genetic testing for men with:

    • Metastatic prostate cancer

    • Very high risk prostate cancer

    • High risk prostate cancer

    • Prostate cancer with regional nodal involvement

  • This is based on two key trials: 

    • Study #1: https://www.nejm.org/doi/full/10.1056/NEJMoa1603144 

      • Studied 692 men with metastatic prostate cancer.

      • Identified 84 deleterious germline DNA-repair gene mutations in 11.8% of the participants (82 men), involving 16 genes.

      • Incidence of these mutations in metastatic cases to be significantly higher (11.8%) than in localized prostate cancer.

      • The frequency of mutations did not vary significantly based on age at diagnosis or family history of prostate cancer. 

    • Study #2: https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.6_suppl.169 

      • Cancer Genome Atlas prostate cancer study,

      • Men with high risk prostate cancer comprising over 90% of the cohort, showed an incidence of roughly 5%. 

Evolution of Prostate Cancer Treatment: 

  • 1940s: Orchiectomy Leads to Tumor Response

  • 1970s-1980s: Introduction of Nonsteroidal Antiandrogen Receptor Antagonists

    • Novel nonsteroidal anti androgen receptor antagonists, including bicalutamide and enzalutamide, emerge. 

  • Mid-1980s-1990s: Maximum Androgen Blockade (MAB) - involves LHRH agonist or surgical castration combined with an androgen receptor antagonist.

  • Early 2000s: Bicalutamide with ADT

    • Bicalutamide (Casodex): Developed as a newer antagonist, combined with ADT becomes the standard of care for first-line treatment in metastatic prostate cancer.

  • At the onset of Castrate-Resistant state, transition to Chemotherapy

  • Early 2000s: Taxanes in Castrate-Resistant Disease

  • 2010: Introduction of Cabazitaxel

  • Modern Era: Integration of Newer Generation Oral Anti-Androgen Medications

    • Setting the stage for trials using newer generation oral anti-androgen medications in combination with ADT.

    • Exploration of first-line chemotherapy options in the evolving landscape of prostate cancer treatment.

Deciding between doublet and triplet therapy 

  • Selecting between doublet and triplet therapy is not very clear; there are no good biomarkers to determine which is best

  • Based on CHAARTED study (discussed below), the concept of high volume disease vs. low volume disease came about. This is one way to decide what to treat patients with. Essentially, trying to spare exposure to chemotherapy (docetaxel) unless it is absolutely needed. 

DOUBLET THERAPY OPTIONS

  • CHAARTED Study: Approval of ADT+docetaxel

    • "Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer." Published in 2015

    • Design:

      • Randomized patients to ADT monotherapy or ADT + docetaxel (6 cycles).

      • Stratified patients based on high volume and low volume disease at randomization.

    • Results: 

      • High volume disease: Improved overall survival by approximately 10 months. 

      • Low volume disease: No significant survival difference. 

    • TFOC Critical Appraisal:

      • Advantages of approach: Fixed duration of therapy, eliminating the need for indefinite treatment with enzalutamide, apalutamide, or abiraterone/prednisone.

      • Impact on Subsequent Trials: Introduction of the concept of high volume disease as a key subgroup in subsequent trials.

      • Clinical Relevance: Significantly influenced the treatment landscape by providing a tailored approach based on disease volume.

  • LATITUDE Study: Approval of Abiraterone (+Pred) + ADT

    • LATITUDE trial phase III RCT that compared ADT monotherapy vs. ADT + abiraterone/prednisone. Published 2017

    • Design: 

      • Randomized patients to ADT+adi/pred vs. ADT+placebo (Note: this was NOT broken down by high or low volume disease) 

    • Results:

      • 15% absolute point improvement in 3-year OS (from 50% to 65%) with the use of abiraterone + prednisone compared to placebo 

    • TFOC Critical Appraisal: 

      • Challenge in interpretation:

        • Poor rates of post-progression therapy in both arms.

        • Critical to assess overall survival benefit in real-world practice.

      • Control group treatment:

        • Consideration: If a drug is approved in later lines and moved to earlier lines, the control group should receive that approved drug at progression.

      • Access to post-progression therapy:

        • <25% of patients in the control arm received appropriate post-progression therapy with ADT monotherapy.

        • Issue: Limited access in several countries due to cost constraints.

      • Real-world implications:

        • Highlights challenges in global trial execution and access to post-progression therapies.

        • Despite limitations, abiraterone + ADT demonstrated an overall survival advantage compared to the non-standard-of-care scenario of no access to abiraterone at all.

  • STAMPEDE trial: Approval of Abiraterone (+Pred) + ADT

    • Design: 

      • Multistage, multiplatform trial design with a dynamic control arm continuously accruing patients and randomizing them. 

      • Featured multiple comparator arms with different therapies.

    • Results (relevant ones for this discussion):

      • Docetaxel + ADT arm:

        • Explored docetaxel + ADT vs. ADT alone in the metastatic setting.

        • Showed improved overall survival but limited to high volume disease.

      • Abiraterone/Pred + ADT arm:

        • Investigated abiraterone/pred + ADT vs. ADT alone in the metastatic setting.

        • Improved overall survival for both high and low volume metastatic disease.

    • TFOC Critical Appraisal: 

      • Post-progression therapy limitations:

        • ADT monotherapy arm had only 73% of patients receiving any therapy after progression.

        • Control arm showed limited usage of abiraterone or enzalutamide for subsequent cancer therapy (approximately 17% of patients).

      • Considerations for Treatment Approach:

        • Abiraterone, less toxic than docetaxel, is a reasonable option but involves indefinite therapy.

        • Suggested approach for high volume disease: Fixed duration docetaxel followed by oral therapy as a cost-effective strategy.

  • ARCHES Trial: Approval of Enzalutamide + ADT

    • Design: Randomized patients to ADT+enzalutamide versus ADT+placebo. 

      • Also had pre-specified subgroup analyses breaking down patients by high vs. low volume AND prior exposure to docetaxel

    • Results: 

      • Survival benefit vs. ADT alone, even in high and low volume disease, and in patients who had prior docetaxel exposure. 

    • TFOC Critical appraisal: 

      • Post-protocol therapy was not reported

  • TITAN Trial: Approval of Apalutamide + ADT

    • Design: Randomized patients to ADT+apalutamide versus ADT+placebo

      • Also had pre-specified subgroup analyses breaking down patients by high vs. low volume AND prior exposure to docetaxel

    • Results: 

      • Survival benefit over ADT, even in high and low volume disease, and in patients with prior docetaxel exposure 

    • TFOC Critical Appraisal: 

      • Post-protocol analysis was an issue, with only 25% of patients getting subsequent hormonal therapy in the ADT arm

TRIPLET THERAPY OPTIONS

  • PEACE-1: Approval of ADT+Docetaxel+Abiraterone 

    • Design: 

      • Patients with de novo metastatic castration-sensitive prostate cancer (n = 1,173).

      • Randomized 1:1:1:1 to receive:

        • Standard of care (ADT + Docetaxel) (n = 296).

        • Standard of care plus abiraterone (n = 292).

        • Standard of care plus radiotherapy (n = 293).

        • Standard of care plus abiraterone plus radiotherapy (n = 292).

    • Results:

      • Co-primary endpoints were radiographic progression-free survival and overall survival.

      • Radiographic progression-free survival significantly improved with abiraterone addition.

      • Overall survival showed a 25% improvement with abiraterone added to androgen-deprivation therapy plus docetaxel.

      • showed benefit limited to the high volume group

    • Additional Findings:

      • Toxicity: Adverse events well balanced, except for hypertension (22% with abiraterone vs. 13% without).

      • Treatment beyond progression: 84% of control arm patients with disease progression received at least one life-prolonging therapy, emphasizing the benefit of earlier use of next-generation hormonal therapy.

  • ARASENS Trial: Approval of ADT+Docetaxel+Darolutamide 

    • Design: 

      • Patients with metastatic hormone-sensitive prostate cancer (1,305 patients from 23 countries)

      • Randomized to receive: Darolutamide (n = 651) in combination with androgen-deprivation therapy (ADT) and docetaxel. Placebo (n = 654) in combination with ADT and docetaxel.

    • Results: 

      • Co-primary endpoints included overall survival.

      • High-Volume Disease

        • Significantly prolonged overall survival compared to the control group (HR = 0.69, 95% CI = 0.57–0.82).

        • Median overall survival was not estimable in the darolutamide group vs 42.4 months in the control group.

      • Low-Volume Disease:

        • Similar trends observed, with the darolutamide group showing improved survival (HR = 0.68, 95% CI = 0.41–1.13).

      • Time to Castration Resistance:

        • Darolutamide group had prolonged time to castration resistance across all subgroups.

    • TFOC Critical Appraisal:

      • ARASENS didn’t report post progression therapy

      • One month treatment for darolutamide is $14,700 USD

The crew behind the magic:

  • Show outline: Vivek Patel

  • Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath

  • Editing: Resonate Recordings

  • Shownotes: Srijan Valasapalli, Ronak Mistry

  • Social media management: Ronak Mistry

We are proud to partner with HemOnc.org!

Want to learn more about the trials that lead to the regimens discussed today? What about dosing schedules? See links in the show notes for a link to HemOnc.org

TheFellowOnCall HemeOncPodcast
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Episode 090: Prostate Cancer Series, Pt. 7- Treatment for Met. Castrate Resistant Prostate Cancer
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Episode 088: Prostate Cancer Series, Pt. 5 - Systemic Treatment for Localized Prostate Cancer