Prostate Cancer Awareness Month: Advances Seen in Screening, Later-line Treatments

Ashley E. Ross, MD, PhD

Major progress has been seen in the diagnosis and treatment of prostate cancer over the past few years.

According to Ashley E. Ross, MD, PhD, an associate professor of urology at Northwestern Medicine, advances have been made in how we detect and determine the extent of prostate cancer disease burden. Much of this has come from the implementation of imaging. This includes the use of multi-parametric MRI prior to initial diagnostic biopsy for men with suspected prostate cancer and additionally the use of PET imaging to determine whether metastatic disease is present.

Further, regarding treatment, precision medicine and targeted therapeutics are playing an increasing role in management of metastatic disease.

In an interview with Targeted Oncology, Ross discusses new prostate cancer screening and staging options as well as therapies for both earlier and later-stage disease. 

TARGETED ONCOLOGY: What most important developments over the past year are reshaping the landscape of diagnosed prostate cancer?

ROSS: Prostate cancer continues to be the most common non-skin malignancy among men. Prior to prostate-specific antigen (PSA)-based screening, a substantial portion of men would present with incurable disease. PSA-based screening allowed for detection of prostate cancer at earlier, curable stages but brought with it concerns about over detection of low-risk disease which could lead to over-treatment. Now with newer technologies, we can limit over detection and by utilizing approaches like active surveillance, we can minimize overtreatment.

Though approaches to prostate cancer screening still begin with a PSA, the PSA is now used to guide other non-invasive testing rather than prompt biopsy. Imaging with multi-parametric MRI of the prostate allows for at least a third of prostate biopsies to be avoided and limits the detection of clinically insignificant prostate cancer without compromising the detection of American Joint Committee on Cancer stage II-IV disease. Randomized controlled trials such as the Stockholm MRI trial reported this year and the PRECISION trial reported a couple years ago solidify that performance of MRI prior to decision to biopsy represents the best standard of care.^1,2

A second advance forward has been in the more accurate staging of prostate cancer once diagnosed. Recently the FDA has approved piflufolastat F 18 (Pylarify) which recognizes prostate-specific membrane antigen (PSMA) for the staging of men considering localized treatment of prostate cancer.

The proPSMA study (ANZCTR12617000005358)³ showed that by using PET-PSMA and replacing less “conventional” imaging modalities such as CT scans and bone scans, we can stage men with prostate cancer 20% to 30% more accurately while reducing their radiation exposure.

What are you looking for in a first-line treatment?

Decisions for first-line treatment, depends on the stage. For favorable risk clinically localized disease (stage I through stage IIB) active surveillance can be considered and for stage I disease it is the preferred option.

For men with intermediate grade and high grade clinically localized cancers (stage IIB, C and some stage III disease) and life expectancies of 10 years, local therapy (i.e. surgery or radiation based approaches are preferred). There are many nuances, particularly if radiation to the prostate is considered as a treatment option. These nuances include determining if hypofractionated radiation can be employed, whether hormonal therapy should be used as an adjunct, and for how long it should be used. There are some interesting trials ongoing in that space being conducted by the National Radiation Oncology Group. Some of these explore enhanced risk stratification with the Decipher genomic classifier to help determine the intensity and duration of androgen deprivation therapy used with radiation. This year we have additionally seen the FDA approval of a new oral androgen deprivation therapy, relugolix. Relugolix appears to allow for more rapid castration and recovery of testosterone when compared to injectable, depot luteinizing hormone-releasing hormone therapies and may be ideal for use in the adjuvant setting for localized disease where treatment durations are finite (HERO trial [NCT03085095]).⁴

Finally, for men with newly diagnosed metastatic disease, first-line treatment decisions are now being somewhat stratified depending on disease burden but across populations, systemic therapy intensification (with androgen signaling inhibitor therapies like abiraterone, apalutamide or enzalutamide, or with chemotherapy such as docetaxel) should be employed and added to androgen deprivation therapy to improve overall survival.^5-7 For men with newly-diagnosed low-volume metastatic disease, there is suggestive data that treatment of their primary tumors in the prostate and possibly metastasis-directed therapy may improve outcomes.

What are the reported advancements for treating later line disease?

Important new considerations for later-line metastatic disease include the use of molecularly targeted therapies. To this end, it is important that we appropriately characterize castration-resistant prostate cancer (CRPC) at the molecular level. Men with metastatic CRPC (mCRPC) should have their genetics evaluated (both somatic genetics and germline genetics). A significant subset of advanced prostate cancer is deficient in its ability to carry out DNA repair through homologous recombination. The PROfound trial (NCT02987543)₈ reported this year demonstrated that, like breast cancer, homologous recombination repair deficient advanced prostate cancer (i.e. those with pathogenic variants in BRCA1, BRCA2 or other genes like PALB2) respond to therapy with the PARP inhibitor olaparib (Lynparza). The TRITON2 trial (NCT02952534)⁹ demonstrated similar results with rucaparib (Rubraca), another PARP inhibitor in men with looked at men with mCRPC. Both olaparib and rucaparib are now FDA approved for selective men with mCRPC.

Beyond PARP inhibitors, we have seen further progress this year for therapies with therapeutic benefit in patients with mCRPC who have undergone multiple treatment lines. Prior to this year, radiopharmaceuticals like radium 223 (Xofigo) had been FDA approved and could increase survival among symptomatic men with mCRPC and bone only involvement. This year we have had reporting of VISION trial (NCT03511664)¹⁰, which examined heavily pretreated with mCRPC who had PET-PSMA scans showing avid tumor uptake regardless of whether disease was only localized to the bone. Men were then randomized to receive 177Lu-PSMA-617 PSMA or standard of care and those receiving the PSMA-targeted radiopharmaceutical experienced an overall survival benefit.

What other targeted therapies are being investigated for men with advanced disease?

In addition to the exploration of novel therapeutics there are lines of intensive investigation into the sequencing of therapies that are known to work and the use of therapeutic combinations. For example, many trials look at using PARP inhibitors as first line, in the hormone sensitive setting, for metastatic disease. Similar investigations are moving PSMA-focused radiopharmaceuticals into earlier lines of therapy. Ongoing investigation is also occurring into immunotherapy into prostate cancer. One such line of research employs PSMA as a target to bring in an immunotherapeutic responses. Pathways long thought to be important in aggressive prostate cancer are also being investigated as targets, for example the PI3 kinase/AKT pathway. Finally, many lines of research focus on developing better biomarkers by which to determine which men will ideally benefit from which therapies and when.

Are there any potential FDA approvals or any trials that you're looking forward to in the next couple months?

The main one would be the 177Lu-PSMA-617 PSMA which was investigated and showed survival benefit in the recently reported VISION trial. FDA approval, while important, is of course just one step in the process. In order to get life prolonging therapies and superior technologies to patients we additionally need insurance companies to update their guidelines and allow patients access. Further, practitioners need to develop awareness of how best to implement these therapies.

What are your final thoughts for Prostate Cancer Awareness Month?

Across the spectrum of prostate cancer diagnosis and treatment, we've seen big advances over the last year and a continual movement towards precision oncology. I am hopeful that with these and ongoing efforts into developing better diagnostic methods and treatments, men with prostate cancer will live longer and better.

_References:

_{1. Nordström T, Jäderling F, Carlsson S, et al. Does a novel diagnostic pathway including blood-based risk prediction and MRI-targeted biopsies outperform prostate cancer screening using prostate-specific antigen and systematic prostate biopsies? - protocol of the randomised study STHLM3MRI. BMJ Open. 2019;9:027816. doi:10.1136/bmjopen-2018-027816}

_{2. Kasivisvanthan V, Rannikko A, Borghi M, et al. MRI-Targeted or standard biopsy for prostate-cancer diagnosis. N Engl J Med. 2018;378:1767-1777. doi:10.1056/NEJMoa1801993}

_{3. Hofman M, Lawrentschuk N, Francis R, et al. 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}

_{4. Shore ND, Saad F, Cookson MS, et al; HERO Study Investigators. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med. 2020;382(23):2187-2196. doi:10.1056/NEJMoa2004325}

_{5. Parker C, James N, Brawley C, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. 2018;392(10162):2353-2366. doi:10.1016/S0140-6736(18)32486-3}

_{6. Chi KN, Agarwal N, Bjartell A, et al; TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307}

_{7. Davis ID, Martin AJ, Stockler MR, et al; ENZAMET Trial Investigators and the New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835.}

_{8. De Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382:2091-2102 doi:10.1056/NEJMoa1911440}

_{9. Abida W, Patnaik A, Campbell D, et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. 2020;38(32):3763-3772doi:10.1200/JCO.20.01035}

_{10. Sartor A, Morris M, Messman R, et al. VISION: An international, prospective, open-label, multicenter, randomized phase III study of 177Lu-PSMA-617 in the treatment of patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020:38(suppl 6):TPS259. doi:10.1200/JCO.2020.38.6_suppl.TPS259}