Episode 085: Prostate Cancer Series: Pt. 2. - Pharmacology
This week, we chat with Vineetha Thomas, PharmD, BCCCP, BCOP who is a clinical pharmacist specializing in genitourinary oncology at the Stevenson Cancer Center at the University of Oklahoma. In this episode, we discuss the ins-and-outs of how Dr. Thomas thinks about the various drugs available to treat prostate cancer and how she counsels her patients.
Thanks to our friends at the Pharmacy Podcast Network for connecting us with Dr. Thomas!
What are the GnRH agonists and how do they work?
Leuprolide, goserelin, tripterelin
Stimulate GnRH receptors on pituitary gland and initially cause an increase in FSH and LH, which in turn cause the testes to produce an initial surge of testosterone
Persistent elevation of GnRH agonist activity leads to down-regulation of GnRH receptors on the pituitary, which eventually leads to decreased testosterone levels
What are the GnRH antagonists and how do they work?
Directly block the GnRH receptors, leading to an immediate reduction in LH, FSH, and testosterone
How do you choose between the drugs?
Whatever is on formulary and/or approved by insurance, most often leuprolide
Degarelix has to be given monthly, while leuprolide can be given less often (see below)
Degarelix has a higher rate of injection site reactions
Oral relugolix can be fairly expensive
In the phase 3 HERO trial that got relugolix approved, there were fewer cardiac events with relugolix than leuprolide
In what doses and frequency is leuprolide available?
7.5 mg IM every month
22.5 mg IM every 3 months
30 mg IM every 4 months
45 mg IM every 6 months
What are the main side effects of androgen deprivation therapy?
Hot flashes
Fatigue
Bone loss (over time)
Long-term cardiovascular events
Loss of muscle mass (over time)
Relugolix requires a loading dose (3 tablets) if missed for more than a week
What are some strategies to prevent hot flashes?
Try non-pharmacological interventions such as keeping the room cooler and wearing layers that can be removed quickly
Could try venlafaxine (starting dose 37.5 mg and increase up to 75 mg)
Anecdotally, some patients tolerated GnRH antagonists much better
How do non-steroidal antiandrogens (NSAA) work and what are their unique side effects?
Competitively inhibit androgen receptor binding to testosterone and prevent translocation of the complex
Enzalutamide and apalutamide can cross the blood brain barrier and cause dizziness and even seizures
Darolutamide does not cross the blood brain barrier and has fewer CNS side effects
How does abiraterone work and what are its unique side effects?
Competitively and irreversibly inhibits CYP17, an enzyme required in the biosynthesis of androgens
Need to monitor liver enzymes as well as potassium level and blood pressure
Baseline comprehensive metabolic panel and then every 2 weeks for the first 3 months, then monthly monitoring
What is the role of prednisone that is concomitantly given with abiraterone?
Blocking CYP17 causes a reduction in serum cortisol and a compensatory increase in ACTH, which can lead to mineralocorticoid side effects like hypertension, edema, and hypokalemia
To mitigate these side effects, low dose prednisone (5 mg) is given with abiraterone
In the castration sensitive setting, prednisone is started at once daily
If a patient is having hypertension or edema, can increase prednisone to twice daily
In the castration resistant setting, prednisone is started at twice daily
Is there a role for dose reduction in abiraterone?
Patients with significant LFT elevations (up to grade 2) should have abiraterone held
Upon normalization of LFTs, can reduce dose down to 750 mg daily and as low as 500 mg daily if necessary
What is the utility of bicalutamide?
Bicalutamide is an oral highly selective androgen receptor antagonist
It can be utilized to block the testosterone surge that occurs in patients starting on GnRH agonists, specifically in the setting of metastases to weight bearing bones or heavy disease burden
Bicalutamide should be started for 7-10 days prior to giving leuprolide and can be discontinued 14 days after leuprolide is given
There is limited utility outside this case scenario in the era of the newer NSAA agents
What is the utility of enzalutamide in the setting of biochemical recurrence?
Based on the recently published EMBARK trial, enzalutamide + androgen deprivation therapy for nine months can be given in patients with high-risk biochemical recurrence to improve metastasis-free survival
What is an important drug-drug interaction (DDI) of enzalutamide?
Enzalutamide has a number of DDIs as it a strong inducer of CYP3A4
Avoid concomitant administration of enzalutamide and the direct oral anticoagulants (DOACs) rivaroxaban or apixaban
What is the current role of cytotoxic chemotherapy in prostate cancer?
Metastatic castration resistant prostate cancer
De novo metastatic castration sensitive prostate cancer with high-volume / high-risk disease
The preferred agent is docetaxel as part of triplet therapy
What is triplet therapy?
This refers to docetaxel added to androgen deprivation therapy and either abiraterone (in the PEACE-1 trial) or darolutamide (in the ARASENS trial)
Darolutamide tends to be tolerated better as abiraterone can overlap with many of the side effects of docetaxel
What is sipuleucel-T (Provenge)?
This is an autologous cancer vaccine used in the metastatic castration resistant setting
Patients have to be asymptomatic or minimally symptomatic
Three days before patient starts, they are sent for leukapheresis for isolation of antigen presenting cells (APCs), which are sent to the manufacturer
The APCs are incubated for 48 hours with prostatic acid phosphatase (present in 95% of prostate cancer cells) and granulocyte-macrophage colony stimulating factor, which helps them to mature
Once the product arrives back, the patient has to return on the same day for infusion because the package expires 3 hours after it is opened!
The APCs should induce an immune response from host T cells
Between the narrow utility and the multiple barriers to use, it is not used very often
What are the side effects of sipuleucel-T?
Very well tolerated overall
There is a hypersensitivity reaction at the time of infusion, which can manifest as hyperpyrexia
The infusion has to be stopped for this, which is an issue given the 3 hour time limit!
Pre-medicate with acetaminophen and diphenhydramine, with meperidine on hand
What is radium-223 (Xofigo)?
This is a radiopharmaceutical agent that is utilized in patients with metastatic castration resistant prostate cancer with bone-only mets
This agent is a calcimimetic agent that binds in the areas of bone metastases
It is given once every 4 weeks for six doses
It is well tolerated overall, but uncommonly can cause mild myelosuppression
What is lutetium-177-PSMA-617 (Pluvicto)?
Lutetium-177 is a radiopharmaceutical agent that has been previously been utilized in patients with neuroendocrine tumors when bound to dotatate, which attaches to somastatin receptors and allows for targeted delivery of beta minus radiation
In prostate cancer, lutetium-177 is bound to prostate specific membrane antigen (PSMA)
Pluvicto is indicated in patients with metastatic castration resistant prostate cancer who have progressed on docetaxel and a NSAA
A PSMA PET scan is performed prior to administration to identify sites of activity
What is the role of DEXA scan and bisphosphonates in patients with prostate cancer?
Androgen deprivation therapy can cause increased bone turnover in the long term
Patients should have baseline bone mineral density evaluation with dual energy X-ray absorptiometry (DEXA) scan
Patients with osteoporosis should be started on a bisphosphonate or denosumab
For osteoporosis, the dose of zoledronic acid is 5 mg annually
For osteopenia, an option is denosumab 60 mg every six months
References:
https://www.nejm.org/doi/full/10.1056/NEJMoa2004325 : HERO Study
https://www.nejm.org/doi/full/10.1056/NEJMoa2303974 : EMBARK Trial
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00367-1/fulltext : PEACE-1 Trial
https://www.nejm.org/doi/full/10.1056/NEJMoa2119115 : ARSENS Trial
The crew behind the magic:
Show outline: Ronak Mistry, Vivek Patel
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Resonate Recordings
Shownotes: Neil Biswas
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
This episode was created in collaboration with our friends at Pharmacy Podcast Network!
