ASCO 2019: Updated Approaches to Treatment Sequencing in the Era of M0 CRPC Approvals

Chicago, IL (UroToday.com) This session was set up and moderated by Mark Fleming, MD, with a specific focus on the general medical oncologist (and urologist). The structure was that of a case presentation, with breaks for discussion and audience participation. Below, I summarize the discussion and the panelists’ input, as well as audience response to the questions asked. As there were no formal presentations by each of the panelists, the topics below are not attributed to any one individual.

The first slide summarized the landscape of currently available options for the treatment of advanced prostate cancer:
ASCO 2019 prostate cancer landscape

The first case is a 65-year-old man (EW) who is spiritually active (important as it affects his decision to get treatment), adopted (but has a twin brother who was also adopted with him), and has a pre-treatment PSA of 22. He has cT3N0M0 disease on conventional imaging. He is NOT interested in clinical trials. He declines surgery and ultimately chooses radiation therapy.

Audience question and response #1: What treatment would you have offered this high-risk advanced non-metastatic patient?

  1. ADT: 8%
  2. Radiation + Abiraterone: 10%
  3. Radiation + ADT: 74%
  4. Radiation + ADT + Docetaxel: 8%
Ian Davis, MBBS, mentioned that surgery would be an option and one that many patients in Australia would have chosen. Danan Rathkopf, MD, noted that radiation + ADT is probably the most appropriate option in the current setting, knowing what we know about the benefit of local therapy now. However, based on STAMPEDE data, it would not be unreasonable to consider the addition of abiraterone. Fred Saad, MD, FRCS, noted that, based on Mason et al. data, the addition of radiation to ADT has important effects: > 2 year OS benefit, and perhaps more importantly, > 5 years delay to treatment progression (=castration resistance).1
ASCO 2019 TTP vs OS

Historically, ADT alone may have been a reasonable option – but in today’s world, the benefit of therapy to the primary is increasingly being recognized.

3-year post-treatment, EW has a BCR with PSA 5.7, PSADT > 12 months. Conventional imaging again negative. The patient decides to manage with prayer alone.

Audience question and response #2: What is your trigger to start ADT?

  1. Absolute PSA level: 9%
  2. PSA kinetics: 72%
  3. Disease evident with novel imaging: 11%
  4. No treatment until cM1 (CT/BS): 8%
Dr. Davis points out that while PSMA is routine in Australia, this is not the case in most places, so C may be impractical at this time. All the panelists agreed with the audience and said PSA kinetics, and in particular, PSA doubling time. This is based on excellent natural history data. D’Amico et al. demonstrated that PSADT in men with BCR have a wide range of prognosis:2

ASCO 2019 PSADT

This was mirrored by data from Partin et al., which also showed a wide range of metastases-free survival depending on Gleason grade, time to recurrence and PSA DT.3

ASCO 2019 gleason scores

PSA doubling times <6 months or <10 months are often used as markers of aggressive disease.

EW now presents again with a PSADT of 8 months and PSA 12.7. He is recommended to start ADT.

Audience question and response #3: What treatment would you offer now with a PSADT <10 months?

  1. ADT continuous: 41%
  2. ADT intermittent: 22%
  3. ADT+ Abiraterone: 32%
  4. No treatment until cM: 13%
The panelists all disagreed with this approach. There is strong evidence to support the non-inferiority of intermittent ADT, as Dr. Saad mentioned. As such, all would have used iADT rather than cADT in this setting, especially if they have a good response to induction. Dr. Rathkopf does note that there is some evidence to support ADT + Abiraterone in this disease space, but none that are approved as of yet – this includes an abstract by Efstathiou et al. at ASCO 2018,4 in which abiraterone + ADT demonstrated a 7 month improvement in PSA-relapse-free survival. However, all panelists agreed that with current data, iADT for BCR is the best option.

EW is put on continuous ADT. He has a good response and has undetectable PSA for 12 months. Then PSA begins to rise (> 2.0). PSAST is now 10 months. Conventional imaging has no metastases. Continues ADT but declines other treatments – wants to rely on prayer alone.

Audience question and response #4: Do you agree that cM0 CRPC exists in 2019?

  1. Agree: 68%
  2. Disagree: 32%
The rapidly changing imaging options, including PSMA PET/CT, is making this a tough question. Most panelists agreed that this disease site does not exist if we look hard enough. But, in 2019, for the most part, it is still a real entity. Dr. Davis first notes that cM0 CRPC comes in many phenotypes, as noted by Smith et al.:5

ASCO 2019 RR for bone mets

A PSADT <6 months, in particular, is associated with an aggressive phenotype.

The panelists note that there are good therapies approved in this setting, and while you can look for radiographic evidence of metastases if it isn’t going to change management drastically, you have to weigh the benefits of these tests. As things are today, you have to look at his clinical picture – if he has slow progression and there is a role for local therapy, PSMA imaging may help. However, with aggressive disease, he probably warrants systemic therapy anyway.

At this time, they took a break from EW and focused on his brother, TW. TW had a radical prostatectomy at age 60, he is otherwise healthy. He underwent salvage XRT for detectable PSA post-operatively. He then was started on AST for BCR, but now has a rising PSA despite ADT. His PSADT is 6 months. Conventional imaging is negative. He meets ARAMIS/PROSPER/SPARTAN criteria. He has more money and is willing to pay out of pocket for any treatment, but not interested in trials.

Audience question and response #5: How would you treat this patient?

  1. Abiraterone + Prednisone: 12%
  2. Apalutamide: 45%
  3. Continue ADT alone: 4%
  4. Darolutamide: 20%
  5. Enzalutamide: 19%
Interestingly, while there was consensus he should get systemic therapy with one of the novel androgen-axis targeted agents, there was a specific focus on apalutamide. The panelists, however, did not feel as strongly. All 3 agreed that any of these agents is good – as long as it tailored for the patient. The following slides compare the main outcomes and side effect profile of the 3 drugs for this patient: (these have been previously reported side by side on urotoday).

MFS:
ASCO 2019 3 drug slide

Overall survival:
ASCO 2019 3 drugs slide OS

Side effects:
ASCO 2019 3 drugs slide side effects

The key take-home points are that the main outcome is now MFS, which has substituted OS and enabled earlier FDA approval. However, OS data is still immature. Dr. Davis does warn against potential lead-time bias with such studies. Dr. Rathkopf’s main point focused on the adverse event profile – you cannot compare these drugs head to head! Rather, you must compare them to their placebo arm. In all 3, they are all pretty well tolerated. Darolutamide, with its different structure, may not cross the blood-brain barrier – and therefore may account for the low “mental impairment” disorders side effect. However, apalutamide and enzalutamide may have more hypertension and fatigue compared to their placebo. Apalutamide, in particular, is associated with a higher rate of rash. These need to be considered independently and tailored to the patient.

TW gets one of the these “lutamides” and has a good response, with a PSA that drops to 0.5 and stays stable for 2.5 years. However, he then begins to have a rise at that time and his PSADT is now 8 months. Conventional imaging is again negative.

Audience question and response #6: Would you be likely to stop the “lutamide” drug?

  1. Most likely: 7%
  2. Fairly likely: 25%
  3. Likely: 21%
  4. Less Likely: 13%
  5. Not likely: 34%
There is a pretty even spread here. The panelists all recommended continuing the lutamide until it came time to change therapy.

TW gets a second opinion at an academic center. They obtain a PSMA PET CT and find 3 bone metastases/lesions. He is asymptomatic. He returns to your care.

Audience question and response #7: Should be now starting a new treatment since metastatic disease is now detected (on novel imaging)?

  1. Strongly agree: 26%
  2. Agree: 30%
  3. Neutral: 10%
  4. Disagree: 17%
  5. Strongly Disagree: 17%
Dr. Rathkopf made an important point – without prior similar imaging, it is uncertain if he had those lesiosn earlier. If it is a new lesion, however, all the panelists favored changing treatment. They cited data by Hadaschik et al. that showed that PSMA PET/CT will be positive nearly 100% of the time in these patients that met Spartan trial criteria (cM0 CRPC):6

ASCO 2019 psma pet

However, in those patients, about 55% have distant metastases, 20% have regional disease and the remainder have local recurrence. So, if you get this novel imaging, expect it to be positive!

Audience question and response #8: What therapy would you recommend next in this asymptomatic patient with conventional imaging negative but novel imaging positive?

  1. Abiraterone + Prednisone: 19%
  2. Continue current therapy: 32%
  3. Docetaxel (or other chemo): 10%
  4. SABR: 33%
  5. Sipaleucel-T: 6%
There was much more variability here among the audience and panel. Panelists did not think continuing the current therapy was appropriate. But they were split amongst the use of abiraterone, docetaxel, and SABR – and would need much more detail about the patient’s kinetics, metastases and status before making a decision. If 3 lesions were localized and could be treated with SABR, that would be a reasonable option. Otherwise, abiraterone or docetaxel would be appropriate. They would have to weigh the volume of disease (low volume favors abiraterone) and concerns for overlapping resistance between androgen-axis targeted agents (favoring docetaxel), but changing systemic therapy would be warranted.

Overall, this was a good session, with good audience participation.

Moderated by: Mark T. Fleming, MD, Chair, Virginia Oncology Associates, US Oncology Research, Virginia, USA

Panelists: Ian Davis, MBBS, Medical Oncologist, Monash University, Melbourne, Victoria, Australia; Dana Rathkopf, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York City, New York; and Fred Saad, MD FRCS, Urologist, Institut du cancer de Montréal, University of Montreal Hospital Research Centre, Montreal, Canada

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @JEFFUrology at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References: 
  1. Mason et al. Final report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer. JCO 2015 Feb 17 [E Pub] 
  2. D’Amico et al. Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst 2003 Sep 17;95(18):1376-83
  3. Partin et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999 May 5;281(17):1591-7. 
  4. Efstathiou et al. A randomized study of finite abiraterone acetate plus leuprolide versus leuprolide in biochemically recurrent non-metastatic hormone naive prostate cancer. ASCO 2018 Oral Presentation. 
  5. Smith et al. Hematopoietic Cell Transplantation for Systematic Mature T-Cell Non-Hodgkin Lymphoma. JCO  2013 Jul 29 [E Pub] 
  6. Hadaschik et al. EAU 2019. 
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