expert roundtables

Treating Castration-Resistant Disease

by Peter R. Carroll, MD, MPH, E. David Crawford, MD, Leonard Gomella, MD, and Neal D. Shore, MD, FACS

Overview

Men with castration-resistant prostate cancer (CRPC) who have no radiological evidence of metastases are, nonetheless, at great risk for developing metastases in the future, and may already have micrometastases that are contributing to a rising prostate-specific antigen (PSA). Expert panelists look to clinical trials for a better understanding of the optimal management of non-overtly metastatic castration-resistant prostate cancer (M0 CRPC). One panelist also touches the potential for increased genetic heterogeneity and decreased responsiveness to therapy of malignancies that are allowed to persist over time.

Q:

What are the different considerations in the initial treatment of advanced disease, particularly in the transition between M0 and M1 CRPC?

Neal D. Shore, MD, FACS

Medical Director and CPI Carolina Urologic Research Center Managing Partner, Atlantic Urology Clinics
Myrtle Beach, SC

Of patients who come to my clinic for the first time with mCRPC, some are within the spectrum are those patients who are M0, whereby radiographic evaluation reveals no demonstrable lesions, and therefore they are identified as having M0 CRPC based upon a rising PSA, usually obtained at least 2 times, with elevations from their nadir level and a demonstrated testosterone level of <50 ng/dL.

“I have been encouraging these patients with M0 CRPC to consider trial enrollment.”

Neal D. Shore, MD, FACS

I have been encouraging these patients with M0 CRPC to consider trial enrollment. We have been participants in the PROSPER [a phase 3 study of enzalutamide in nonmetastatic (M0) castration-resistant prostate cancer (CRPC) patients] and now the ARAMIS [efficacy and safety study of BAY1841788 (ODM-201) in men with high-risk non-metastatic castration-resistant prostate cancer] trial.

These 2 trials were designed to randomize patients in a 2:1 fashion, to receive enzalutamide vs placebo in the PROSPER; and darolutamide (also known as ODM-201) in the ARAMIS trial. The SPARTAN trial has completed enrollment (as has the PROSPER) and was looking at apalutamide, also in the M0 CRPC population.

These 3 trials – PROSPER, SPARTAN, ARAMIS – all have the same primary endpoint, which is metastasis-free survival. There is no approved medication for patients who have M0 CRPC.

Q:

Are there any presentations of advanced prostate cancer that are inherently castration-resistant, ie, resistant to ADT from the very start?

Leonard Gomella, MD

Chairman, Department of Urology
Bernard W. Godwin, Jr. Professor of Prostate Cancer
Sidney Kimmel Medical College
Sidney Kimmel Cancer Center
Thomas Jefferson University
Philadelphia, PA

Most of those cases would likely have a very high Gleason score, with neuroendocrine differentiation, that tend not to respond to androgen ablation alone. Almost all initial metastatic prostate cancer – at least for a certain period of time – responds to hormones, unless you have a lot of neuroendocrine differentiation that doesn’t follow any of the normal hormonal responsive rules.

Peter R. Carroll, MD, MPH

Ken and Donna Derr – Chevron Distinguished Professor
Taube Family Distinguished Professor in Urology
Department of Urology
UCSF - Helen Diller Comprehensive Cancer Center
University of California, San Francisco
San Francisco, CA

Just to take a step backward, with respect to presentations of advanced prostate cancer, the 2 big groups we are dealing with are advanced prostate cancer at presentation, or with initial therapy, and then those patients who relapse after therapy. In the United States, in a PSA-screened population, only about 2% of patients present with de novo metastatic disease. Most patients who present with metastatic disease in this country are patients who were thought to have localized disease under one initial therapy and then relapse.

E. David Crawford, MD

Professor of Urology
University of California, San Diego
Former, Distinguished Endowed Professor of Surgery, Urology, and Radiation Oncology
Head, Section of Urologic Oncology
University of Colorado Anschutz Medical Campus
Aurora, CO

With respect to hormonal-refractory disease, I think we have created this castrate-resistant arena, a lot of it, by taking patients who have biochemical failure after a local therapy and treating them with ADT, having a drop in the PSA, feeling good about it, and then seeing the PSA rise again. The resulting disease tends to fall into this category of M0 CRPC.

We wait for the transition from M0 to M+ CRPC, and that is the point at which all of the new treatments are used. As we are well aware, the longer the cancer is around, the more genetic heterogeneity exists, and the less responsive it is to therapy. And there is movement of the therapies earlier in steps – eg, from post-chemo to pre-chemo, etc. I believe that is where the future is.

“We wait for the transition from M0 to M+ CRPC, and that is the point at which all of the new treatments are used.”

E. David Crawford, MD

Now, with respect to M1 CRPC, as Dr Gomella mentioned in an earlier discussion, we published a paper recently in Urology, relating some of the consensus findings from RADAR II (Radiographic Assessments for Detection of Advanced Recurrence – II) where we looked at therapeutic layering, and I think that’s where the excitement is. As evidenced by data from the LATITUDE and STAMPEDE trials, new insights on effective therapeutic layering strategies continue to emerge.

If we think of every type of cancer that we cure, it’s usually not the result of sequential monotherapy, ie, “chemotherapy A followed by chemotherapy B followed by chemotherapy C,” but rather putting agents together in combinations, like CHOP for lymphomas and combinations for testicular cancer and treatments for leukemia. It’s not one drug – it’s multiple drugs. And we’ve got new drugs that are all different, and so the idea of putting them together is challenging, but it’s also exciting.

Peter R. Carroll, MD, MPH

Ken and Donna Derr – Chevron Distinguished Professor
Taube Family Distinguished Professor in Urology
Department of Urology
UCSF - Helen Diller Comprehensive Cancer Center
University of California, San Francisco
San Francisco, CA

I think the treatment considerations here are going to also depend on the disease state, locoregional vs distant metastases, the number of sites, and the biology. This is where these molecular markers such as androgen-receptor splice variant 7 messenger RNA (AR-V7) come in to define the biology. Germ line testing with hormonal-refractory disease has given us some insight into patients who may be candidates for poly ADP ribose polymerase (PARP) inhibitors. For advanced imaging and molecular profiling, disease state, and symptoms, all of these things are taken into account when choosing treatment. I think that, as a result, we are starting to have more precise recommendations based on much better evidence than in the past.

References

A study of apalutamide (ARN-509) in men with non-metastatic castration-resistant prostate cancer (SPARTAN). [NCT01946204]. https://clinicaltrials.gov/ct2/show/NCT01946204. Accessed August 8, 2017.

Crawford ED, Petrylak DP, Shore N, et al. The role of therapeutic layering in optimizing treatment for patients with castration-resistant prostate cancer (prostate cancer radiographic assessments for detection of advanced recurrence II) [RADAR II]. Urology. 2017;104:150-159.

Efficacy and safety study of BAY1841788 (ODM-201) in men with high-risk non-metastatic castration-resistant prostate cancer (ARAMIS) [NCT02200614]. https://clinicaltrials.gov/ct2/show/NCT02200614. Accessed August 8, 2017.

Fizazi K, Albiges L, Loriot Y, et al. ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer. Expert Rev Anticancer Ther. 2015;15(9):1007-1017.

Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. [LATITUDE] N Engl J Med. 2017;27;377(4):352-360.

Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941;1:293.

Hussain M, Fizazi K, Saad F, et al. PROSPER: a phase 3 study of enzalutamide in nonmetastatic (M0) castration-resistant prostate cancer (CRPC) patients. J Clin Oncol. 2016;34:(suppl 2S):Abstract 250.

James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. [STAMPEDE]. New Engl J Med. 2017;27;377(4):338-351.

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