Experts Develop New Guideline for Advanced Prostate Cancer

The 2020 (American Urological Association) AUA Virtual Experience included expert insight on the new AUA Guideline for Advanced Prostate Cancer from 2 experts on the panel that created the guideline.¹

In their discussion during the AUA virtual platform, William Lowrance, MD, MPH, investigator, Huntsman Cancer Institute and associate professor, Division of Urology, University of Utah in Salt Lake City; and Michael S. Cookson, MD, professor and chairman Department of Urology, the Stephenson Cancer Center and University of Oklahoma College of Medicine in Oklahoma City, highlighted the core components of the consensus guideline for urologists to follow in their daily practice.

“The primary aim of this guideline is to assist clinicians with decision-making. The evidence-based guideline recommendations are furnished according to disease state across the entire continuum of advanced prostate cancer,” said Lowrance, who served as chair of the panel.

The focus of the guideline is patients who have exhausted all local therapy options and now require systemic treatment options. These include patients with biochemical recurrence, metastatic hormone-sensitive prostate cancer (mHSPC), nonmetastatic CRPC, and metastatic CRPC. The guideline grades the strength of evidence as high (A), moderate (B), and low or very low (both under the umbrella of C).

Early Evaluation and Counseling

The guideline lays out principles that should be followed with the early evaluation and counseling of patients with suspicion of advanced prostate cancer who do not yet have histologic confirmation. Lowrance said a tissue diagnosis from the primary tumor or metastatic site should be obtained by the clinician.

When diagnosis is confirmed, the guideline recommends physician-patient discussions of treatment options that cover these factors: patients’ tumor characteristics, life expectancy, comorbidities, and treatment preferences. The treatment strategy should, if possible, include a multidisciplinary approach. Also, when possible, pain control and other symptom support should be optimized, explained Lowrance.

Biochemical Recurrence Without Metastatic Disease

In the hormone-sensitive setting, PSA recurrence almost always precedes clinical detection of metastases,” said Lowrance. Thus, in men with biochemical recurrence without metastases, clinicians should perform serial PSA measurements, clinical evaluations, and staging evaluations.

For these staging evaluations, the guideline recommends use of standard-of-care imaging, comprising bone scans and axial imaging with CT or MRI. Given the emergence of advanced PET imaging in the paradigm for advanced prostate cancer, the guideline stipulates that, “Clinicians may utilize novel PET-CT scans in patients with PSA recurrence after failure of local therapy as an alternative to conventional imaging or in the setting of negative conventional imaging.”

In those patients with a rising PSA whose imaging does not reveal any metastases, the guideline recommends that the patients be offered observation or enrollment on a clinical trial. As routine practice, androgen deprivation therapy (ADT) should not be started in these patients.

mHSPC

The guideline states that genetic counseling and germline testing should be offered to all men with mHSPC, regardless of age and family history. The germline testing in this setting focuses on genes that influence homologous recombination repair, such as BRCA1, BRCA2, and ATM.

Patients with mHSPC should be offered surgical castration or ADT combined with either LHRH agonists or antagonists (grade B). Further, grade A evidence supports the guideline recommendation that “clinicians should offer continued ADT in combination with
either androgen pathway–directed therapy (eg, abiraterone acetate [Zytiga] plus prednisone; apalutamide [Erleada]; or enzalutamide [Xtandi]) or docetaxel-based chemotherapy,” said Lowrance.

Lowrance, shared some of the data supporting the use of androgen pathway–directed therapies in this setting. In the phase 3 TITAN trial (N = 1050), apalutamide plus ADT reduced the risk of death by 33% versus ADT alone in patients with mHSPC (HR, 0.67; 95% CI, 0.51-0.89; P = .005).² And the phase 3 ENZAMET trial (N = 1125), showed the same 33% reduction in the risk of death with enzalutamide plus ADT versus ADT alone in patients with mHSPC (HR, 0.67; 95% 0.52-0.86; P = .002).³

Nonmetastatic CRPC

This population comprises patients with a rising PSA but no sign of metastatic disease on standard imaging despite “the persistence of a castrate-level testosterone,” said Cookson.

In recent years, the first agents have been specifically approved by the FDA for the treatment of these patients, based on a demonstrated metastasis-free survival (MFS) benefit. All 3 therapies are androgen receptor antagonists: apalutamide, darolutamide (Nubeqa), and enzalutamide.

Apalutamide, enzalutamide, and darolutamide all demonstrated an MFS benefit over placebo in the pivotal SPARTAN (HR, 0.28; P <.001),⁴ PROSPER (HR, 0.29; P <.001),⁵ and ARAMIS (HR, 0.41; P <.001)⁶ trials, respectively. All 3 trials enrolled over 1200 patients with nonmetastatic CRPC at high risk for developing metastatic disease (PSA doubling time of ≤10 months). Cookson noted that since the completion of the data analysis for the guideline, overall survival (OS) data from the PROSPER trial were published showing that enzalutamide led to a 27% reduced risk of death versus placebo, with a median OS of 67 versus 56.3 months, respectively (HR, 0.73; 95% CI, 0.61-0.89; P = .001).⁷

mCRPC

Docetaxel is indicated for the first-line treatment of patients with mCRPC with several treatments approved for use before and after the chemotherapy. The immunotherapy sipuleucel-T (Provenge) is approved by the FDA for asymptomatic or minimally symptomatic mCRPC. Enzalutamide and abiraterone acetate (plus prednisone) are approved for use both in chemotherapy-naïve patients and following failure of docetaxel. The chemotherapy cabazitaxel (Jevtana) is approved as a second-line, post-docetaxel option.

The radiopharmaceutical radium-223 (Xofigo) is approved for the treatment of patients with CRPC with symptomatic bone metastases but no known visceral metastatic disease. In this setting, radium-223 has demonstrated an OS benefit over standard therapy in both chemotherapy-naïve patients and those with prior docetaxel.

Genetic testing and related treatments are a burgeoning area of the mCRPC paradigm as research has shown that, “DNA damage response (DDR) alterations have been identified in 23% of patients with mCRPC, including both somatic and germline defects. Among the DDR alterations, BCRA2 is the most frequently altered, and these gene alterations are expected to confer sensitivity to PARP inhibitors; thus, nearly 20% of patients with mCRPC may potentially benefit from this therapy,” explained Cookson.

The AUA guideline includes the grade C recommendation that, “Clinicians should offer a PARP inhibitor to patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated mCRPC following prior treatment with enzalutamide or abiraterone acetate, and/or a taxane-based chemotherapy. Platinum-based chemotherapy may be offered as an alternative for patients who cannot use or obtain a PARP inhibitor.”

Two PARP inhibitors were recently approved by the FDA for the treatment of patients with mCRPC. In May 2020, the FDA approved rucaparib (Rubraca) for the treatment of adult patients with BRCA mutation (germline and/or somatic)–associated mCRPC who have been treated with androgen receptor–directed therapy and a taxane-based chemotherapy. The approval was based on data from the phase 2 TRITON2 study, in which the confirmed objective response rate was 44% in a cohort of 62 patients with BRCA-mutated mCRPC.⁸

Also in May 2020, the FDA approved olaparib (Lynparza) for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone acetate. The approval was supported by the phase 3 PROfound trial, in which the risk of disease progression or death was reduced by 66% with olaparib compared with abiraterone acetate or enzalutamide (HR, 0.34; P <.0001) in patients with BRCA1/2- or ATM-mutant mCRPC.⁹

The final option for mCRPC that Cookson covered was the immune checkpoint inhibitor pembrolizumab, which is available as an option for patients with microsatellite instability-high or mismatch repair–deficient tumors.

Bone Health

Cookson concluded the discussion with a focus on bone health. Preventative treatments with bisphosphonates or denosumab should be recommended to patients with advanced prostate cancer whose bone loss has put them at high fracture risk, according to the guideline. It is also indicated that, when appropriate, these patients should be referred to experts in the area of osteoporosis. Among patients with mCRPC with bony metastases, the guidelines include the grade B recommendation that, “Clinicians should prescribe a bone protective agent, denosumab or zoledronic acid, to prevent skeletal-related events,” said Cookson.

References

1. Cookson MS, and Lowrance W. AUA Guidelines 2020: Advanced Prostate Cancer. Presented at: 2020 AUA Virtual Experience. June 27-28, 2020.

2. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. doi: 10.1056/NEJMoa1903307

3. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381:121-131. doi: 10.1056/NEJMoa1903835

4. Smith MR, Sadd F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408-1418. doi:10.1056/NEJMoa1715546

5. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378:2465-2474. doi:10.1056/NEJMoa1800536

6. Fizazi K, Shore N, Tammela TL. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380:1235-1246. doi: 10.1056/NEJMoa1815671

7. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med.2020;382:2197-2206. doi:10.1056/NEJMoa2003892

8. Rubraca (Rucaparib) approved in the U.S. as monotherapy treatment for patients with BRCA1/2-mutant, metastatic castration-resistant prostate cancer (MCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy Press release. Clovis Oncology. May 15, 2020. Accessed June 25, 2020. https://bit.ly/2z0rMrK

9. Lynparza highlights of prescribing information. FDA. Updated May 19, 2020. Accessed June 28, 2020. https://bit.ly/2WLJt7u.