Advances allow for more accurate detection of metastatic disease.
The case (provided by Raoul S. Concepcion, MD, FACS)
To contextualize the rapidly evolving landscape of evaluation of patients with prostate cancer, consider a case example: A 62-year-old White man presents for consultation due to an elevated prostate-specific antigen (PSA) of 8.2 ng/dL that was confirmed on repeat testing. He has no prior values available for comparison.
Symptomatically, he has an American Urological Association symptom score of 11 without other complaints. His past medical history is unremarkable with only hypertension, for which he takes amlodipine 5 mg daily and a baby aspirin. He’s undergone a laparoscopic cholecystectomy. He has no known drug allergies and is married with 2 healthy adult male children. Notably, his family history includes prostate cancer in his father (diagnosed at aged 58 years and alive) and breast cancer in his paternal grandmother (diagnosed at aged 50 years and now deceased from the disease).
On physical examination, the prostate is estimated at 50 grams, symmetric, and without nodules or induration. The patient undergoes a prebiopsy multiparametric MRI scan, which demonstrates a prostate volume of 65.3 cc and a PI-RADS (Prostate Imaging Reporting and Data System) 4 lesion at the right peripheral zone (base, 1.2 cm). He then undergoes a fusion biopsy; the pathologic results show:
Target lesion: 2/3 cores (+), grade group (GG) 4, approximately 65% involved
Systematic Bx: 6/12 cores (+)
R base: 2/2 cores (+), GG 4, approximately 70% involved
R mid: 1/2 cores (+, GG 4, < 50% involved
R apex: 1/2 cores (+), GG 3, < 50% involved
L base: 2/2 cores (+) GG 3, approximately 60% involved
This patient has newly diagnosed cT1c prostate cancer, which is very high risk—according to the National Comprehensive Cancer Network (NCCN) criteria—because of the presence of more than 4 cores of GG 4 disease.
As we evaluate this patient, our goal is to accurately determine his current and future risk of disease spread to inform treatment, prognosis, and counseling. Current guidelines recommend staging with conventional imaging (CT or MRI, and bone scan) as well as genetic testing. However, advances in staging imaging are allowing more accurate detection of metastatic disease and play an increasingly large role in other parts of the world, with adoption in the United States expected to follow.
Guideline-concordant conventional imaging in patients with high- and very high–risk disease includes abdominopelvic cross-sectional imaging, often a CT scan, and a technetium-99m methylene diphosphonate bone scintigraphy scan. Multiparametric MRI (mpMRI) has emerged in the past 5 to 10 years as a common staging imaging modality, and NCCN guidelines endorse the superiority of mpMRI compared with abdominopelvic CT for staging.1
For this patient, we would follow a current guideline–based approach and complete his staging with a nuclear medicine bone scan to complement his mpMRI. If the bone scan is negative for evidence of metastasis, he falls into a group of men with apparently localized disease who are at high risk for recurrence despite appropriate primary therapy, likely due to the inability of conventional imaging to identify small metastases at low PSA. Closing this gap in diagnostic accuracy is an area of active research.
Newly published data suggest that advanced imaging techniques using PET-CT may complement or supplant conventional imaging in the near future. The use of PET-CT
in prostate cancer in the US has been led, to date, by the approval of 3 radiotracers in the management of recurrent or metastatic prostate cancer: choline C 11, sodium fluoride F 18, and fluciclovine F 18 (Axumin). Newer prostate-specific membrane antigen (PSMA)–based tracers including gallium 68 (68Ga) and DCFPyL F 18 are increasingly being used, first in Australia and Europe and now in the US. These PSMA-based tracers are the subject of several recent clinical trials that support the diagnostic superiority of PSMA PET-CT over conventional and previously approved advanced imaging modalities.
PSMA is a cell surface glycoprotein that is highly overexpressed in most prostate cancer cells. Multiple recent studies have added to the growing body of evidence supporting the use of PSMA PET-CT across the prostate cancer disease spectrum. The proPSMA study was a multicenter clinical trial of patients with high-risk prostate cancer who were randomized to receive conventional imaging vs 68Ga PSMA PET-CT for the purposes of pretreatment staging.2 The investigators found that 68Ga PSMA PET-CT had a 27% greater area under the curve for diagnostic accuracy when compared with conventional imaging, driven by its improved sensitivity (85% vs 38%) and specificity (98% vs 91%). Use of PSMA PET-CT was more likely to effect a significant change in management versus conventional imaging (28% vs 15%, respectively). For this patient, PSMA PET-CT may be more likely to identify small regional or distant metastatic disease that, if found, may influence our treatment decision.
Although proPSMA compared 68Ga PSMA PET-CT to conventional imaging, Calais et al compared fluciclovine F 18 PET-CT with 68Ga PSMA PET-CT in the biochemical recurrence setting among men with PSA lower than 2 ng/mL.3 The indication for imaging in this study was different from proPSMA. Here, imaging was used to detect recurrent disease, whereas proPSMA examined the pretreatment staging setting. The investigators demonstrated that PSMA PET-CT had higher detection rates at low PSA compared with fluciclovine F 18, adding to the evidence of the superior sensitivity of PSMA-based PET-CT over fluciclovine F 18 PET-CT.3
A pair of recently published trials, OSPREY and CONDOR, led to the recent FDA approval of F18-DCFPyL (Pylarify), another novel radiotracer used for PSMA-targeted PET-CT, for both initial staging and biochemically recurrent disease.
The multicenter phase 2/3 OSPREY study enrolled 2 cohorts to evaluate the diagnostic performance of DCFPyL F 18 PET-CT: Cohort A—most relevant to our patient—enrolled men with high-risk prostate cancer undergoing radical prostatectomy with pelvic lymphadenectomy to assess its accuracy detecting prostate cancer in the pelvic lymph nodes; cohort B enrolled patients with suspected recurrent or metastatic disease on conventional imaging who then underwent tissue biopsy. In cohort A, DCFPyL F 18 PET-CT had a median specificity of 98%, sensitivity of 40%, positive predictive value (PPV) of 87%, and negative predictive value (NPV) of 83% for detecting pelvic nodal involvement. The performance of DCFPyl F 18 PET-CT was superior compared to conventional imaging with CT/MRI by most measures (3-fold higher PPV: 87% vs 28%, respectively), higher specificity (98% vs 65%), slightly higher NPV (83% vs 78%), and similar sensitivity (40% vs 43%).4
The multicenter phase 3 CONDOR study enrolled men with biochemical recurrence after definitive therapy with negative or equivocal conventional imaging and again found that DCFPyL F 18 PET-CT had PPV of 80% to 90% and that 64% of participants experienced a change in intended management after undergoing DCFPyL F 18 PET-CT.5
There are some advantages and disadvantages to the different radiotracers from a technical perspective that may guide their real-world adoption. First, as highlighted in the data from Calais and colleagues, 68Ga PSMA PET-CT outperforms fluciclovine F 18 PET-CT.3 Further, 68Ga was the first well-described PSMA-based radiotracer and has, therefore, garnered significant research interest. However, 68Ga requires specialized generators with batch production of 2 to 4 patient doses per generator elution and has a physical half-life of approximately 1 hour, which requires studies to be performed locally because central production with delivery to remote centers would be challenging. On the other hand, F 18–labeled PSMA tracers such as DCFPyL F 18 offer some advantages over 68Ga, namely large-scale radiosynthesis, allowing for a larger number of patient studies; a longer half-life of nearly 2 hours, which could enable centralized production with delivery to more remote centers; and increased maximum spatial resolution due to its lower positron energy than 68Ga.
On December 1, 2020, the FDA approved 68Ga PSMA PET-CT for staging in men with prostate cancer with suspected metastasis before initial definitive therapy and in men with biochemical recurrence, although the approval is, at this time, limited to UCLA and UCSF. DCFPyL F 18 (Pylarify) received FDA approval in May 27, 2021. Although, at this time, NCCN guidelines would not recommend the use of these advanced imaging techniques until after conventional imaging is performed and found to be negative, this may be rapidly changing. The dissemination and availability of DCFPyL F 18, expected to reach routine clinical use towards the end of 2021 dependent on identification of regional radiopharmacies to provide radiotracer, is expected to rapidly bring PSMA imaging from sparse research and clinical trial settings to routine clinical use though this will, as always in US health care, depend on insurer reimbursement decisions.
In addition to staging investigations, another important consideration for this patient is the use of genetic testing. For patients with high- or very high–risk disease, NCCN guidelines recommend germline genetic testing, and contemporary testing may offer actionable information for physicians and patients. BRCA1/2 mutations, if found, may hold prognostic information; studies have demonstrated that prostate cancer patients with BRCA mutations have higher Gleason scores, nodal involvement, metastatic disease, and worse survival.6 In patients with metastatic disease, genetic testing for mutations in homologous recombination repair genes is required to determine suitability for treatment with PARP inhibitors, such as olaparib (Lynparza) or rucaparib (Rubraca). In addition, pembrolizumab (Keytruda) is approved for use in tumors with microsatellite instability or mismatch repair–deficiency, so approximately 5% of metastatic castration-resistant prostate cancer cases could qualify.
Genetic testing is also important for family counseling. Relatives of a patient with a known BRCA1/2 mutation may be at increased risk for breast, ovarian, pancreatic, colon, and prostate cancer. Data from the IMPACT study7 suggest that patients with BRCA1/2 mutations may benefit from annual PSA screening earlier than noncarriers or using a lower PSA cutoff value.
In this case, the patient’s high-risk disease and positive family history of prostate cancer in his father, diagnosed at a relatively young age, may also point toward a genetic predisposition and support the utility of the recommended germline testing. Although access to genetic counseling remains challenging at many centers and has limited broader adoption, its use is guideline recommended and should be a priority for these patients.
The diagnostic and treatment landscape across the spectrum of disease states in prostate cancer continues to rapidly evolve, as highlighted by this case. In the near future, we will hopefully better understand when and how to use these advanced tests as well as the implications for patient outcomes and survival.
Tallman is a urology resident, Wallis is a urologic oncology fellow, and Scarpato is an assistant professor of urology at the Vanderbilt University Medical Center in Nashville, Tennessee.
1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 2.2021. Accessed March 17, 2021. https://www.nccn.org/professionals/physician_gls/pdf/prostate_blocks.pdf
2. Hofman MS, Lawrentschuk N, Francis RJ, et al; proPSMA Study Group Collaborators. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet. 2020;395(10231):1208-1216. doi:10.1016/S0140-6736(20)30314-7
3. Calais J, Ceci F, Eiber M, et al. 18 F-fluciclovine PET-CT and 68 Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial. Lancet Oncol. 2019;20(9):1286-1294. doi:10.1016/S1470-2045(19)30415-2
4. Pienta KJ, Gorin MA, Rowe SP, et al. A phase 2/3 prospective multicenter study of the diagnostic accuracy of prostate-specific membrane antigen PET/CT with 18 F-DCFPyL in prostate cancer patients (OSPREY). J Urol. Published online February 26, 2021. doi:10.1097/JU.0000000000001698
5. Morris MJ, Rowe SP, Gorin MA, et al. Diagnostic performance of 18 F-DCFPYL-PET/CT in men with biochemically recurrent prostate cancer: results from the CONDOR phase 3, multicenter study. Clin Cancer Res. Published online February 23, 2021. doi:10.1158/1078-0432.CCR-20-4573
6. Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882
7. Eeles RA, Bancroft E, Page E, Castro E, Taylor N. Identification of men with a genetic predisposition to prostate cancer: targeted screening in men at higher genetic risk and controls—The IMPACT study. J Clin Oncol. 2013;31(suppl 6):12. doi:10.1200/jco.2013.31.6_suppl.12