Greater Consensus From Global Experts on Controversies in Prostate Cancer

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In late August, experts from around the globe convened in Basel, Switzerland, at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC) to discuss controversial areas related to the management of advanced prostate cancer. Although the full proceedings of the conference will be published in the future in a peer-reviewed journal, for now, readers of The ASCO Post can see a preview of both the areas of consensus and the areas still under debate.

Charles Drake, MD, PhD

Charles Drake, MD, PhD

In an interview with The ASCO Post, panel member and presenter at the APCCC Charles Drake, MD, PhD, discussed the areas of emerging consensus, the areas that are still “up in the air,” and the areas where consensus is breaking down, as well as the rationale for those designations. Dr. Drake is Director of Genitourinary Oncology and Co-Director of Cancer Immunotherapy at NewYork-Presbyterian/Columbia University Medical Center, New York.

“The conference this year was the best one yet,” Dr. Drake explained. “Partly, that comes from repeated iterations. It was well organized, with much better attendance than the first two consensus conferences, which are held every other year. For 2 days, we listened to a panel of speakers who had 10 minutes of ‘fame,’ each on different topics with no digressions—only state-of-the-art and current clinical data related to advanced prostate cancer.”

In previous years, there seemed to be more areas of lack of consensus, according to Dr. Drake. “With emerging data and greater experience with new drugs and technologies, there are many more areas where consensus is beginning to gel.”

Emerging Consensus

Consensus appears to be reached on the need to treat the primary cancer in the setting of newly diagnosed metastatic prostate cancer, based on data from the STAMPEDE trial. “For patients with low-burden disease, generally fewer than five metastases, we now agree that treating the primary with radiation improves survival in the setting of ongoing androgen-deprivation therapy. This is based on solid data,” Dr. Drake commented.

The question related to treating the primary lesions was specific, as were all the questions participants voted on. For example, “After surgery, should you radiate the prostate bed always, sometimes, never.”

“Members of the audience are, in many cases, asked to extrapolate from the available data and vote. The questions very much involve real-world decisions,” he added.

The use of advanced imaging, particularly prostate-specific membrane antigen (PSMA) positron-emission tomography (PET), is another area of emerging consensus in the setting of patients treated with surgery and radiation who have a rising PSA level but no metastatic disease on conventional imaging. Emerging consensus on this use of PSMA PET is based on reasonably clear data that this technology will have clinical utility in that setting. The data are not from level 1 evidence, but they are from published series and experience.

“It’s fairly well agreed upon that the relative sensitivity and specificity of PSMA PET in this setting is useful,” Dr. Drake stated.

A third area of emerging consensus is the use of next-generation antiandrogens in nonmetastatic high-risk castration-resistant prostate cancer and metastatic castration-resistant prostate cancer. Three clinical trials provide level 1 evidence for this approach: SPARTAN trial (apalutamide), PROSPER trial (enzalutamide), and ARAMIS trial (daralutamide). The drugs are approved in the metastatic castration-resistant prostate cancer setting.

Consensus ‘Up in the Air’

The importance of obtaining genetic data is becoming clearer, but exactly how to obtain those data is still under discussion. “There is emerging consensus around germline testing, which can be done fairly easily on blood and saliva, but there is less consensus around whether you need both germline and somatic testing,” Dr. Drake continued. “Exactly how valuable genetic testing is in prostate cancer may depend on the outcome of phase III trials of targeted agents such as PARP [poly (ADP-ribose) polymerase] inhibitors,” he said.

Somatic tumor cell testing is limited by the challenges of obtaining tumor samples in every patient. It is also limited by the lack of ability to perform next-generation sequencing in various locations around the world. Still, tumor testing is likely to be of value, since germline testing will miss half the patients with DNA repair defects.

Along these lines, the anti–PD-1 (programmed cell death protein 1) agent pembrolizumab has been approved for solid tumors with microsatellite instability (MSI), which is seen in about 2% of patients with prostate cancer. But how actionable is testing for MSI?

“We don’t know the response rate for PD-1 blockade in patients with prostate cancer and MSI. One small retrospective study from Memorial Sloan Kettering Cancer Center showed that the response rates in prostate cancer are lower than in other cancers,” Dr. Drake said.

Consensus Eroded

With more than eight drugs now approved for the treatment of metastatic castration-resistant prostate cancer, the choice of drug is much less clear (eg, cabazitaxel vs docetaxel, abiraterone acetate vs enzalutamide vs apalutamide vs daralutamide).

“For advanced prostate cancer, we’ve learned a few things. For example, it was clear from the ENZAMET trial that combining enzalutamide plus chemotherapy in the first-line setting does not improve outcomes. Also, smaller studies have shown that the combination of enzalutamide and abiraterone does not appear to be additive, and the combination of radium-223 and abiraterone is not well tolerated,” Dr. Drake continued.

“In the not-too-distant past, men with metastatic castration-resistant prostate cancer had only a handful of choices—chemotherapy or sipuleucel-T. It is harder now to build consensus on which drug to use first and how best to sequence them. There are no real head-to-head trials, and there will not be. This is where consensus begins to erode. It is the natural outcome of a plethora of emerging approvals, which is a good thing,” according to Dr. Drake.

Without hard data to guide treatment selection, the oncologist’s clinical experience with a particular drug will influence decision-making. Insurance coverage and drug formularies will also influence the choice of treatment.

“With all these new drugs for metastatic castration-resistant prostate cancer, making a choice without side-by-side comparisons is more complicated,” he said. “There are really no level 1 data to help a clinician choose between enzalutamide and abiraterone.”

APCCC Proceedings: Areas of Controversy

The final publication of APCCC proceedings will cover 10 areas of controversy: locally advanced prostate cancer; biochemical recurrence after local therapy; management of the primary tumor in the metastatic setting; newly diagnosed castration-sensitive/naive prostate cancer, including oligometastatic prostate cancer management; management of metastatic castration-resistant prostate cancer; bone metastasis; molecular characterization of tissue and blood; heterogeneity of patients with prostate cancer; and side effects of hormonal treatment and management. 

DISCLOSURE: Dr. Drake owns stock or other ownership interests in Compugen, Harpoon Therapeutics, Kleo Pharmaceuticals, and Tizona Therapeutics, Inc; has served as a consultant or advisor to AstraZeneca/MedImmune, Bristol-Myers Squibb, Compugen, Janssen Oncology, Merck, Pfizer, Pierre Fabre, Potenza Therapeutics, Roche/Genentech, and Tizona Therapeutics Inc; has received institutional research funding from Bristol-Myers Squibb; holds institutional patents licensed to Bristol-Myers Squibb and institutional patents licensed to Potenza Therapeutics; and has been reimbursed for travel, accommodations, and other expenses by the American Association for Cancer Research, ASCO, Merck Sharp & Dohme, Pfizer, and Roche/Genentech.