From September 10 to 13, 2021, the American Urological Association (AUA) presented its annual conference, AUA2021. This year’s virtual experience included a range of cutting-edge research on metastatic prostate cancer, which is a disease that is on the rise. According to data from the Centers for Disease Control and Prevention, more than 8% of men living with prostate cancer will experience distant or metastasized disease.1
Neal D. Shore, MD, FACS, US chief medical officer of Surgery and Oncology and director and certified principal investigator at the Carolina Urologic Research Center, Myrtle Beach, South Carolina, provided his perspective on the newest research focused on metastatic prostate cancer presented at AUA2021.
Which of the presentations at AUA2021 did you find to be most interesting or clinically impactful with regard to metastatic prostate cancer?
We saw important data come across regarding the VISION trial (ClinicalTrials.gov Identifier: NCT03511664)2 and the importance of ushering in a new class of medication, prostate-specific membrane antigen-targeted radioligand therapy. The novel mechanism of action of this class will certainly be additive to our existing life-prolonging, approved prostate cancer indications. Like so many other approved indications, clinical trials will provide a great opportunity to look at combination therapies as well.
Can you describe the results of your post-hoc analysis of the ARCHES trial3 (ClinicalTrials.gov Identifier: NCT02677896), and what do these conclusions mean for physicians treating patients with metastatic prostate cancer?
Importantly, patients who present with metastatic castration-sensitive prostate cancer (mCSPC) — whether low volume or high volume — absolutely will benefit from intensified therapy or combination therapy. These patients really should no longer receive only androgen deprivation therapy (ADT) as monotherapy.
We have several studies that have demonstrated, through phase 3 trial methodology, that combining testosterone suppression with docetaxel, or with enzalutamide, apalutamide, or abiraterone acetate, not only delays radiographic progression but enhances survival. ARCHES further demonstrated that, regardless of tumor burden — high-volume or low-volume — and regardless whether the patient received an early first-generation androgen receptor inhibitor, such as bicalutamide, there was no difference in the benefit of delaying progression for patients who received ADT and enzalutamide compared with those who received ADT monotherapy only.
Importantly, at the ESMO [European Society for Medical Oncology] Congress 2021,4 we’ll present conclusive evidence that overall survival, as a key secondary endpoint, has also been met in ARCHES. [Editor’s note: This interview with Dr Shore was conducted prior to ESMO 2021.]
Researchers described second-line antiandrogens as contributing to extended survival in metastatic prostate cancer but noted that median overall survival improved by only 4 months.5 What role do these drugs play in improving overall survival in the population with metastatic prostate cancer?
Historically, many of our urologist and medical oncologist colleagues have been comfortable sequencing novel hormonal agents, specifically abiraterone, enzalutamide, apalutamide, and darolutamide. But what we recognize is, regardless when the androgen receptor axis drug is given — either as a first-line or second-line therapy in mCSPC— when a patient experiences progression after an adequate course of one androgen receptor inhibitor, they do not benefit from sequencing to another androgen receptor inhibitor. These patients will do much better if they are given the opportunity to choose another approved, survival-prolonging agent that has a novel mechanism of action — for example, one of the taxanes; a radiopharmaceutical such as radium-223; immunotherapy such as sipuleucel-t; or a poly (ADP-ribose) polymerase inhibitor such as olaparib or rucaparib.
Results of one study reported in an AUA2021 abstract6 showed that overall and cancer-specific survival rates were similar in regard to radiotherapy to the prostate and no local therapy. Given those findings, should physicians shift the focus to radiotherapy, or must other factors be considered before making this kind of determination?
In the STAMPEDE trial (ClinicalTrials.gov Identifier: NCT00258476), patients received a combination of ADT and an androgen receptor inhibitor plus localized radiation for a total of 37 Gy. The investigators looked at low-volume compared with high-volume disease and found clear demonstration that patients benefited from getting radiation to the prostate, despite having low-volume mCSPC.
This finding has also been amplified in recent presentations of data from the PEACE1 trial7 (ClinicalTrials.gov Identifier: NCT01957436). I think it’s important that physicians have a full and thorough discussion with patients who have low-volume mCSPC to consider radiation to the prostate. We don’t, as of yet, have data to support prostatectomy, but there are ongoing trials evaluating this as an option as well.
A group of researchers evaluated the process of balancing efficacy with toxicity in docetaxel in treating metastatic castration-resistant prostate cancer.8 They identified 3 risk categories that correlated with overall survival. Do you believe that this prediction model is sufficient for balancing treatment efficacy and toxicity? What changes might you make when evaluating this risk in your own patients?
I think that docetaxel is an extremely active agent, and perhaps, given the recent pandemic, we’ve moved away from using docetaxel, given that it is clinic-required therapy that is delivered intravenously.
Also, there are some grade 3/4 toxicities that are very manageable; however, they are real risks, particularly neutropenia, febrile neutropenia, and even neuropathy, which can develop after chronic utilization of more than several cycles.
The rest of the adverse effects are actually manageable and well tolerated. Because docetaxel is a highly active drug, we see both prostate-specific antigen responses and palliative responses, and it is clearly survival-prolonging. I do think that the same is certainly a considerable advantage of using cabazitaxel for patients who have experienced progression on docetaxel.
Based on some of the data that we’ve seen from the TITAN trial (ClinicalTrials.gov Identifier: NTCT02489318) and from ARCHES, among patients who received docetaxel and then entered the trials of mCSPC in those studies, as well as in PEACE1, there seems to be an advantage to triple therapy, especially for patients who have high-volume disease.
I think the verdict is still out regarding a paradigm change in our clinical management of triple therapy, but it is becoming more and more encouraging, especially for patients with high-volume disease for whom there might be additional biomarkers that can better inform whether to amplify or intensify therapy. Docetaxel and abiraterone are generic drugs, so this becomes an additional advantage for many of our colleagues and patients throughout the world.
Any final thoughts about the AUA2021 conference?
There was a lot of great energy and effort that went into preparing the virtual conference, with about 3 weeks’ time to create a completely virtual meeting. I am appreciative of the staff who made that happen and of the faculty and the presenters who were able to pivot so successfully.
These are the types of things that we all have to become not only nimble about but also patient with, as it relates to dealing with the pandemic.
- During the COVID-19 pandemic, oncologists might have moved away from prescribing docetaxel because of its intravenous route of delivery and potential for adverse effects. However, many of these adverse effects are manageable and well tolerated, and the benefits — in terms of prostate-specific antigen and palliative responses — might outweigh future toxicity concerns.
- When a patient experiences progression after receiving an adequate course of androgen receptor inhibitor therapy, sequencing to another androgen receptor inhibitor might not be appropriate. Instead, these patients may do better on another approved survival-prolonging agent, such as radium-223, sipuleucel-t, or olaparib or rucaparib.
- Regardless of tumor volume, patients with mCSPC should no longer receive monotherapy ADT only.
The Q&A was edited for clarity and length.
Neal D. Shore, MD, FACS, reported affiliations with Amgen, Inc.; Astellas Pharma Inc.; AstraZeneca; Bayer AG; Bristol Myers Squibb; Dendreon Pharmaceuticals; Ferring Pharmaceuticals; Janssen Biotech, Inc.; Merck & Co; Myovant Sciences; Pfizer; Roche Holding AG; and Tolmar Holdings, Inc.
- Siegel DA, O’Neil ME, Richards TB, Dowling NF, Weir HK. Prostate cancer incidence and survival, by stage and race/ethnicity—United States, 2021-2017. MMWR Morb Mortal Wkly Rep. 2020;69(41):1473-1480. doi:10.15585/mmwr.mm6941a1
- Morris MJ, De Bono JS, Chi KN, et al. Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol. 2021;39(18 suppl):Abstract LBA4. doi:10.1200/JCO/2021.39.15_suppl.LBA4
- Shore ND, Iguchi T, Villers A, et al. Enzalutamide in metastatic hormone-sensitive prostate cancer patients who received prior antiandrogen therapy: post hoc analysis of ARCHES. Abstract PD34-07. J Urol. 2021;206(suppl 3):e585.
- Armstrong AJ, Iguchi T, Azad AA, et al. Final overall survival (OS) analysis from ARCHES: a phase III, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) + androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC). Abstract LBA25. Presented at: ESMO Congress 2021; September 18, 2021.
- Kim I, Jang T, Skim S, et al. Modest increase in survival among patients with metastatic prostate cancer in the second-line antiandrogen therapy era. Abstract MP32-09. J Urol. 2021;206(suppl 3):e568.
- De Bleser E, Lumen N, Buelens S, et al. Newly-diagnosed low-volume metastatic prostate cancer; is there a place for cytoreductive radical prostatectomy? Abstract MP24-10. J Urol. 2021;206(suppl 3):e415-e416.
- Fizazi K, Maldonado X, Foulon S, et al. A phase 3 trial with a 2×2 factorial design of abiraterone acetate plus prednisone and/or local radiotherapy in men with de novo metastatic castration-sensitive prostate cancer (mCSPC): First results of PEACE-1. J Clin Oncol. 2021;39:(suppl 15):5000. doi:10.1200/JCO.2021.39.15_suppl.5000
- Martini A, Cirulli G, Parikh AB, et al. Balancing efficacy and toxicity of docetaxel in patients with metastatic castration-resistant prostate cancer. Results from a pooled analysis of three prospective randomized trials. Abstract MP24-09. J Urol. 2021;206(suppl 3):e415.
Posted by Haymarket’s Clinical Content Hub. The editorial staff of Renal and Urology News had no role in this content’s preparation.
Reviewed September 2021