AUA Guidelines 2020: Advanced Prostate Cancer

( The American Urological Association 2020 Virtual Annual Meeting was highlighted by an update on the AUA guidelines for advanced prostate cancer, presented by William Lowrance, MD, MPH, and Michael Cookson, MD. Dr. Lowrance notes that this guideline was produced by a multidisciplinary panel with representation from the AUA, ASCO, ASTRO, and SUO as well as a patient advocate. Their systematic review was conducted from 1998 through January 20, 2020, and 192 publications were identified through an initial search, with an additional 46 carried over from the prior AUA CPRC review. During an additional updated review, 26 studies were added to the cohort of studies comprising this guideline.

The statement of evidence rating used for the guideline is as follows:

  • A (High): Very confident that the true effect lies close to that of the estimate of the effect
  • B (Moderate): Moderately confident in the effect estimate, whereby the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
  • C (Low): Confidence in the effect estimate is limited, whereby the true effect may be substantially different from the estimate of the effect
  • C (Very Low): Very little confidence in the effect estimate, whereby the true effect is likely to be substantially different from the estimate of the effect
Dr. Lowrance also provided the following key definitions used by the panel:

  • Biochemical recurrence without metastatic disease: A rise in prostate-specific antigen (PSA) in prostate cancer patients after treatment with surgery or radiation (PSA of 0.2 ng/mL and confirmatory value of 0.2 ng/mL or greater following radical prostatectomy and a nadir + 2.0 ng/mL following radiation); this may occur in patients without symptoms. 
  • Hormone-sensitive prostate cancer: Prostate cancer that has either not yet been treated with ADT or is still responsive to ADT
  • Castration-resistant prostate cancer: Disease progression despite ADT and a castrate level of testosterone (<50 ng/dL); progression may present as either a continuous rise in serum PSA levels (values identified at a minimum of 1-week intervals with minimal value of 2.0 ng/mL, with estimations of PSA doubling time with at least 3 values measured ≥4 weeks apart), the progression of pre-existing or new radiographic disease, and/or clinical progression with symptoms. 
  • High-volume metastatic disease: Presence of visceral metastases and/or greater than or equal to four bone metastases with at least one outside the vertebral column and pelvis. 
  • High-risk metastatic disease: Disease that has a poorer prognosis in the presence of two or three of the following high-risk features: Gleason ≥8, ≥3 bone lesions, or measurable visceral metastases. 
As the therapeutic landscape evolves to include increasingly complex combinations of systemic therapies with or without local therapies, advances in imaging, and germline and somatic testing, treating men with advanced prostate cancer is increasingly one that must embrace multidisciplinary management approaches. This team includes the urologist, medical oncologist, radiation oncologist, pathologist, genetic counselor, and palliative care specialists. Management of patient’s symptoms and quality of life are of great concern to the patients and their families. Physicians caring for patients with advanced disease should manage symptoms such as pain, urinary symptoms, and sexual function, as well as side effects of treatment.
In the hormone-sensitive setting, PSA recurrence almost always precedes the clinical detection of metastases. This often involves serial PSA measurements, clinical evaluation, and staging evaluations. Clinicians may utilize novel PET-CT scans in patients with PSA recurrence after the failure of local therapy as an alternative to conventional imaging or in the setting of negative conventional imaging (Expert Opinion):


Guideline 7 suggests that for patients with a rising PSA after local therapy and no demonstrated metastatic disease by conventional imaging, clinicians should offer an observation or clinical trial enrollment (Clinical Principle). Guideline 8 notes that ADT should be routinely initiated in this population (Expert Opinion), however, if ADT is initiated in the absence of metastatic disease, intermittent ADT may be offered in lieu of continuous ADT (Conditional Recommendation, Grade B).

With regards to patients with metastatic hormone-sensitive prostate cancer, Guideline 13 states that patients, regardless of age and family history, should be offered genetic counseling or germline testing (Expert Opinion). Guideline 14 notes that clinicians should offer ADT with either LHRH agonists or antagonists or surgical castration for these men (Strong Recommendation, Grade B). In patients with metastatic hormone-sensitive prostate cancer, Guideline 15 states that clinicians should offer continued ADT in combination with either androgen pathway directed therapy (abiraterone plus prednisone, apalutamide, enzalutamide) or chemotherapy (docetaxel) (Strong Recommendation, Grade A). This recommendation is based on the treatment effect seen when ADT is combined with docetaxel (CHAARTED,1 STAMPEDE2), abiraterone plus prednisone (LATITUDE,3 STAMPEDE4), apalutamide (TITAN5), or enzalutamide (ARCHES,6 ENZAMET7).

Dr. Cookson then discussed metastatic castration-resistant prostate cancer, noting that since the approval of docetaxel, there have been 10 additional agents that show either an overall or metastases-free survival benefit (M0) and are now FDA approved on the bases of randomized controlled trials. These agents now include those directed at the androgen receptor, androgen production, chemotherapy, radionuclide therapy, and immunotherapy:

  • Abiraterone acetate + prednisone
  • Apalutamide
  • Cabazitaxel
  • Darolutamide
  • Enzalutamide
  • Olaparib
  • Pembrolizumab
  • Radium-223
  • Rucaparib
  • Sipuleucel-T

Dr. Cookson notes that men with a rising PSA but no visible metastatic disease on conventional imaging despite castration represent a uniquely distinct disease state. Serial PSAs are typically performed every 3-6 months, and conventional imaging every 6-12 months. Until recently, there were no specific agents specifically FDA approved for the treatment of men with M0 CRPC, however, three androgen receptor antagonists successfully prolonged MFS when compared to placebo in men on continued ADT in this setting: apalutamide (SPARTAN8), darolutamide (ARAMIS9), and enzalutamide (PROSPER10). Additionally, recently presented at the ASCO 2020 virtual annual meeting, all three studies showed survival benefit, including PROSPER (HR 0.73, 95% CI 0.61-0.89) publishing there results in the New England Journal of Medicine.11

Over the last 15 years, there has been tremendous advancement in the metastatic castration-resistant prostate cancer (mCRPC) disease space. In 2004, docetaxel was approved as first-line chemotherapy for mCRPC based on a 24% reduction in death compared to mitoxantrone in the TAX-327 study.12 In 2010, results of the IMPACT trial were published, noting that Sipuleucel-T had a 22% reduction in mortality for asymptomatic or minimally symptomatic men with mCRPC who were pre-chemotherapy.13 Subsequently, both enzalutamide (PREVAIL14) and abiraterone + prednisone (COU-AA-30215) showed a survival benefit in pre-chemotherapy patients. Both agents also showed benefit in the post-chemotherapy setting: enzalutamide (AFFIRM16) and abiraterone (COU-AA-30117). ALSYMPCA subsequently showed that patients receiving radium-223 had a survival benefit;18 patients in the TROPIC study also had a 30% survival benefit among patients receiving secondary line cabazitaxel.19

Much attention has recently been directed towards the impact of DNA repair gene alterations found in patients with mCRPC. Up to 23% of these patients harbor DDR alterations, with 8% harboring DDR germline mutations. Among these mutations, BRCA2 is the most frequently altered (12.7%), and alterations in these genes are expected to confer sensitivity to PARP inhibitors, suggesting that nearly 20% of heavily pre-treated mCRPC patients may potentially benefit from this therapy. In the PROfound study, patients treated with olaparib had a median PFS of 7.4 months compared to 3.6 months for the control group,20 leading to recent FDA approval. Of note, rucaparib is also FDA approved for deleterious BRCA mutations based on the TRITON2 study (abstract only).

Guideline 33 notes that clinicians should offer a PARP inhibitor to mCRPC patients with deleterious or suspected deleterious germline or somatic homologous recombination repair mutations following prior treatment with enzalutamide or abiraterone acetate, and/or taxane-based chemotherapy. Platinum-based chemotherapy may be offered as an alternative for patients who cannot use or obtain a PARP inhibitor (Moderate Recommendation, Grade C). Guideline 34 states that in patients with mismatch repair-deficient or microsatellite instability-high mCRPC, clinicians should offer pembrolizumab (Moderate Recommendation, Grade C). In advanced prostate cancer patients at high fracture risk due to bone loss, Guideline 37 suggests that clinicians should recommend preventative treatments with bisphosphonates or denosumab and referral to physicians who have familiarity with the management of osteoporosis when appropriate (Clinical Principle). Finally, Guideline 38 suggests that clinicians should prescribe a bone-protective agent (denosumab or zoledronic acid) for mCRPC patients with bony metastases to prevent skeletal-related events. (Moderate Recommendation, Grade B).

Presented by: William T. Lowrance, MD, MPH, University of Utah, Salt Lake City, UT and Michael Cookson, MD, University of Oklahoma, Oklahoma City, OK

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md, at the 2020 American Urological Association (AUA) Annual Meeting, Virtual Experience #AUA20, June 27- 28, 2020.


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