EAU PCa 2018: mCRPC: Which Drugs and in What Sequence?

Milan, Italy (UroToday.com) Dr. Cornford gave an overview of the therapy for metastatic castrate resistant prostate cancer (MCRPC). CRPC is defined as disease progression despite castrate levels of testosterone (<=50 ng/dl). Failure of androgen deprivation therapy (ADT) occurs due to sustained androgen receptor signaling despite castrate levels of testosterone. In the state of CRPC the androgen receptor signaling pathway is reactivated by changes to the underlying biology of prostate cancer cells. Some of these changes include androgen receptor overexpression, continuation of androgen production despite castration, mutations in the androgen receptor gene, tyrosine kinase signaling, upregulation of androgen receptor co-activators, and androgen receptor splice variants.

Dr. Cornford continued and gave some data on non-metastatic CRPC patients. These patients have no metastases detected on their bone scans and CT imaging. It is still unclear which patients will go on to develop metastases, and whether these patients might benefit from earlier treatment. In the recently published PROSPER trial, 1401 men with non-metastatic CRPC were randomized to either placebo or to daily 160 mg of enzalutamide. (1) The primary endpoint was metastasis free survival, and secondary endpoints included time to pain progression, time to first antineoplastic therapy, time to PSA progression, and quality of life assessment. The median metastasis free survival was 36.6 months in the enzalutamide arm compared to 14.7 months in the placebo arm, p<0.001 (Figure 1). All other secondary endpoints also demonstrated a clear advantage to the enzalutamide treated patients.

Another study published this year (the SPARTAN trial) randomized 1207 non-metastatic CRPC patients to either placebo or daily 240 mg of Apalutamide. (2) The primary endpoint was metastases free survival, and the secondary endpoints included overall survival, time to symptomatic progression, time to cytotoxic therapy, progression free survival, time to metastasis, adverse events, pharmokinetics, and quality of life issues. As in the PROSPER study, a clear advantage was seen favoring the apalutamide arm with a higher metastasis free survival, and a hazard ratio of 0.28! p<0.001.

All other secondary endpoints also demonstrated a clear advantage for the apalutamide group, with overall survival almost reaching statistical significance, p=0.07.
Some important points to be remembered from these two trials were then discussed by Dr. Cornford. All patients in these studies had a PSA doubling time of <=10 months. Additionally, the imaging modalities used are important as they may enable us to see or not see metastases that we might be able to see on other modalities. Early treatment may be more important than delayed treatment. We need to watch out for side effects of these drugs, both expected and novel. Lastly, it is not clear how we are altering the disease biology with these early treatments.

The next topic discussed was patients with metastatic CRPC. Past studies assessing the added benefit of docetaxel (TAX 327), Sipuleucel-T (IMPACT), Cabazitaxel (TROPIC), abiraterone (COU-AA-301, and COU-AA 302), enzalutamide (PREVAIL and AFFIRM), and radium 223 (ALSYMPCA) to these patients have all shown a modest overall survival advantage, ranging between 2.2 months and 4.8 months.

Currently, first line treatment for metastasis CRPC patients who are asymptomatic is either abiraterone or enzalutamide. For symptomatic patients, treatment includes either abiraterone, enzalutamide, docetaxel or radium 223. So how do we know which therapy to administer to which patient, as the available evidence does not provide us with a clear pathway. Dr. Cornford believes that it is usually advisable to start with the most effective therapy with the least toxicity. We should switch to other treatments only if there is clear evidence of resistance. It is important to maximize the length and number of treatments. Lastly, referring patients to clinical trials is most important and will enable us to have more level one evidence in the future. When deciding between abiraterone and enzalutamide, there are several considerations that should sway us to one direction and not the other. The following should make us choose abiraterone over enzalutamide: history of falls, gait problems, neurologic issues, significant baseline fatigue, mild baseline pain, and polypharmacy. In contrast, the following should make us prefer enzalutamide over abiraterone: baseline congestive heart failure, baseline edema, renal impairment, and diabetes.

The St. Gallen advanced prostate cancer consensus conference (APCCC) in 2015 provided us with recommendations on how to manage patients with advanced prostate cancer. First, these patients should be seen every 2-3 months in the clinic. They should undergo a clinical and physical examination. Blood tests should be done for every visit, including PSA, CBC, liver function tests, alkaline phosphatase, renal function tests and urine test and culture. Second, every 6 months these patients should undergo a bone scan and CT of the chest, abdomen, and pelvis. Third, treatment should be changed based on the presence of two of the following: PSA progression, radiographical progression, and clinical deterioration.

Second line treatment for MCRPC patients who have had previous androgen receptor therapy (ART) should include either docetaxel or radium 223. For patients who have had previous therapy with docetaxel, the options include cabazitaxel, abiraterone, enzalutamide, or radium 223.

There has been some debate on the correct sequencing of treatment in MCRPC patients. An international multicenter retrospective study looked at this exact question and divided patients into 3 groups. Group 1 was treated with docetaxel, cabazitaxel and ART. Group 2 was treated with docetaxel, ART, and cabazitaxel. Finally, group 3 was treated with ART, docetaxel, and cabazitaxel. (3) The results demonstrated that groups 1 and 2, that began treatment with docetaxel had a higher median overall survival compared to group 3, as seen in figure 3. Overall survival was significantly shorter when docetaxel was used after a novel ART (hazard ratio of 1.98 (95% C.I 1.32-2.89, p=0.002). Toxicities were similar between the three groups. Although the results of this study are interesting, we need to bear in mind its limitations: its retrospective nature, the small number of patients in group 3 (55) compared to group 1 (158) and group 2 (456), and whether the percentage of fit patients was equal in all three groups.

Lastly, the genomic landscape of MCRPC needs to be considered as well. Robinson et al. (4) has shown that 23% of MCRPC patients harbor DNA repair alterations., Additionally, 2.7% of these patients harbor mismatch repair alterations, and this frequency increases with disease progression. Pritchard et al. (5) demonstrated that 11.8% of men with metastatic prostate cancer have a germline alteration in 16 DNA damage repair genes. This unique genomic landscape will have an impact on the treatment these patients are given in the future.

Dr. Cornford concluded his talk by mentioning that a recent publication showed that the addition of Olaparib (a PARP inhibitor) to abiraterone demonstrated a clear advantage in radiographic progression free survival when compared to abiraterone +placebo. The hazard ratio was 0.65 (95% C.I. 0.44-0.97), p=0.034. (6)

Speaker: P. Cornford, Liverpool (GB)

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter:@GoldbergHanan at the 2nd EAU Update on Prostate Cancer (PCa18)– September 14-15, 2018 – Milan, Italy

References:

1. Hussain M et al. NEJM 2018; 2465-74
2. Smith MR et al. NEJM 2018; 378: 1408-18
3. Delanoy N et al. Eur Urol Oncol 2018
4. Robinson D et al. Cell 2015; 161:1215-28
5. Pritchard CC et al. NEJM 2016; 375:443-53
6. Clarke N et al. Lancet Oncol 2018; 19:975-86
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